Adrenergics and Adrenergic- Blocking Agents

CHAPTER ONE

Adrenergics and Adrenergic-Blocking Agents

ROBERT K. GRIFFITH

School of PharmacyWest Virginia UniversityMorgantown, West Virginia

Burger’s Medicinal Chemistry and Drug DiscoverySixth Edition, Volume 6: Nervous System AgentsEdited by Donald J. AbrahamISBN 0-471-27401-1 © 2003 John Wiley & Sons, Inc.

Contents

1 Introduction, 22 Clinical Applications, 2

2.1 Current Drugs, 22.1.1 Applications of General Adrenergic

Agonists, 92.1.2 Applications of �1-Agonists, 122.1.3 Applications of �2-Agonists, 132.1.4 Applications of �-Agonists, 142.1.5 Applications of Antiadrenergics, 142.1.6 Applications of Nonselective �-

Antagonists, 152.1.7 Applications of Selective �1-

Antagonists, 152.1.8 Applications of �-Antagonists, 162.1.9 Applications of �/�-Antagonists, 162.1.10 Applications of Agonists/Antagonists,

162.2 Absorption, Distribution, Metabolism, and

Elimination, 162.2.1 Metabolism of Representative

Phenylethylamines, 162.2.2 Metabolism of Representative

Imidazolines and Guanidines, 182.2.3 Metabolism of Representative

Quinazolines, 192.2.4 Metabolism of Representative Aryl-

oxypropanolamines, 193 Physiology and Pharmacology, 21

3.1 Physiological Significance, 213.2 Biosynthesis, Storage, and Release

of Norepinephrine, 223.3 Effector Mechanisms

of Adrenergic Receptors, 253.4 Characterization of Adrenergic

Receptor Subtypes, 254 History, 26

1

5 Structure-Activity Relationships, 285.1 Phenylethylamine Agonists, 28

5.1.1 R1 Substitution on the Amino Nitrogen,28

5.1.2 R2 Substitution � to the BasicNitrogen, Carbon-2, 28

5.1.3 R3 Substitution on Carbon-1, 295.1.4 R4 Substitution on the Aromatic Ring,

29

5.1.5 Imidazolines and Guanidines, 305.1.6 Quinazolines, 315.1.7 Aryloxypropanolamines, 32

6 Recent Developments, 336.1 Selective �1A-Adrenoceptor Antagonists, 336.2 Selective �3-Agonists, 34

1 INTRODUCTION

In both their chemical structures and biologi-cal activities, adrenergics and adrenergic-blocking agents constitute an extremely var-ied group of drugs whose clinical utilityincludes prescription drugs to treat life-threatening conditions such as asthma andhypertension as well as nonprescription med-ications for minor ailments such as the com-mon cold. This extensive group of drugs in-cludes synthetic agents as well as chemicalsderived from natural products that have beenused in traditional medicines for centuries.Many adrenergic drugs are among the mostcommonly prescribed medications in theUnited States, including bronchodilators,such as albuterol (13) for use in treatingasthma, and antihypertensives, such as ateno-lol (46) and doxazosin (42). Nonprescriptionadrenergic drugs include such widely used na-sal decongestants as pseudoephedrine (5) andnaphazoline (29). Most of these varied drugsexert their therapeutic effects through actionon adrenoceptors, G-protein-coupled cell sur-face receptors for the neurotransmitter nor-epinephrine (noradrenaline, 1), and the adre-nal hormone epinephrine (adrenaline, 2).

Adrenoceptors are broadly classified into �-and �-receptors, with each group being further

subdivided. Identification of subclasses of adre-noceptors has been greatly aided by the tools ofmolecular biology and, to date, six distinct �-ad-renoceptors (�1A, �1B, �1D, �2A, �2B, �2C), andthree distinct �-adrenoceptors (�1, �2, �3) havebeen clearly identified (1), with conflicting evi-dence for a fourth type of � (�4) (1–3). In generalthe most common clinical applications of �1-ago-nists are as vasoconstrictors employed as nasaldecongestants and for raising blood pressure inshock; �2-agonists are employed as antihyper-tensives; �1-antagonists (�-blockers) are vasodi-lators and smooth muscle relaxants employed asantihypertensives and for treating prostatic hy-perplasia; �-antagonists (�-blockers) are em-ployed as antihypertensives and for treating car-diac arrhythmias; and �-agonists are employedas bronchodilators. The most novel recent ad-vances in adrenergic drug research have beendirected toward development of selective �3-ago-nists that have potential applications in treat-ment of diabetes and obesity (4–8).

2 CLINICAL APPLICATIONS

2.1 Current Drugs

U.S. Food and Drug Administration (FDA)-approved adrenergic and antiadrenergic drugscurrently available in the United States aresummarized in Table 1.1, which is organizedin general according to pharmacological mech-anisms of action and alphabetically withinthose mechanistic classes. Structures of thecurrently employed drugs are given in Tables1.2–1.6 according to chemical class. Drugs in agiven mechanistic class often have more thanone therapeutic application, and may or maynot all be structurally similar. Furthermore,drugs from several different mechanisticclasses may be employed in a given therapeu-

Adrenergics and Adrenergic-Blocking Agents2

Tab

le1.

1A

dre

ner

gic

and

An

tiad

ren

ergi

cP

har

mac

euti

cals

Cla

ssan

dG

ener

icN

ame

Tra

deN

amea

Ori

gin

ator

Ch

emic

alC

lass

Dos

ebc

Gen

eral

agon

ists

Am

phet

amin

e(3

)A

dder

all,

Dex

edri

ne

Smit

hK

line

&F

ren

chP

hen

ylet

hyl

amin

e5–

60m

g/da

yD

ipiv

efri

n(4

)P

ropi

ne

Klin

geP

hen

ylet

hyl

amin

e1

drop

2�

daily

0.1%

soln

.E

phed

rin

eer

yth

ro-(

5)va

riou

sP

hen

ylet

hyl

amin

e50

–150

mg/

day

for

asth

ma

10–2

5m

gi.v

.for

hyp

oten

sion

Epi

nep

hri

ne

(2)

Adr

enal

ine

Par

ke-D

avis

Ph

enyl

eth

ylam

ine

0.3–

1.5

mg

s.c.

2–10

�g/

min

i.v.

160–

250

�g

inh

.M

eph

ente

rmin

e(6

)W

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ine

Wye

thP

hen

ylet

hyl

amin

e30

–45

mg,

i.m.

Nor

epin

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Ster

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Ph

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day

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day

Met

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mot

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350

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min

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eth

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g,2�

daily

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h.

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buta

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(22)

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mg/

day

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ser

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day

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(43)

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mg/

day

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daily

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48)

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–20

mg/

day

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loxy

prop

anol

amin

e2.

5–10

mg/

day

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Fac

tsan

dC

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ns

2002

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ted.

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furt

her

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rmat

ion

con

sult

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ren

ce(1

4).

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Tab

le1.

2P

hen

ylet

hyl

amin

es(S

tru

ctu

res

1–28

)

Com

poun

dR

1R

2R

3R

4R

ecep

tor

Act

ivit

ya

(1)

HH

OH

3�,4

�-di

OH

��

�(2

)C

H3

HO

H3�

,4�-

diO

H�

��

(3)

HC

H3

HH

(��

�)b

(4)

CH

3H

OH

3�,4

�-di

-O2C

C(C

H3) 3

(��

�)c

(5)

CH

3C

H3

OH

H(�

��

)d

(6)

CH

32,

2-di

CH

3O

HH

(��

�)b

(7)

HC

H3

OH

3�,4

�-di

OH

�(8

)H

CH

3O

H3�

-OH

�(9

)H

CH

3O

H2�

,5�-

diO

CH

3�

(10)

CO

CH

2N

H2

HO

H2�

,5�-

diO

CH

3�

(11)

CH

3H

OH

3�-O

H�

(12)

H2-

CH

3,2

-CO

2H

H3�

,4�-

diO

H�

2c

(13)

C(C

H3) 3

HO

H3�

-CH

2O

H,4

�-O

H�

2

(14)

C(C

H3) 3

HO

H3�

,4�-

bis(

O2C

C4H

4-p

-CH

3)

�2

c

(15)

HO

H3�

-NH

CH

O,4

�-O

H�

2

(16)

CH

(CH

3) 2

CH

2C

H3

OH

3�,4

�-di

OH

�(1

7)C

H(C

H3) 2

HO

H3�

,4�-

diO

H�

(18)

C(C

H3) 3

HO

H3�

,5�-

diO

H�

2

(19)

C(C

H3) 3

HO

H2�

-aza

,3�-

CH

2O

H,4

�-O

H�

2

(20)

CH

3O

H4�

-OH

�2

6

(21)

HO

H3�

-CH

2O

H,4

�-O

H�

2

(22)

C(C

H3) 3

HO

H3�

,5�-

diO

H�

2

(23)

H2-

CH

3,2

-CO

2H

H4�

-OH

nae

(24)

CH

3H

3�-S

O2N

H2,4

�-O

CH

3�

1-b

lock

er

(25)

CH

(CH

3) 2

HO

H4�

-NH

SO2C

H3

�-b

lock

er(2

6)H

OH

3�-C

ON

H2,4

�-O

H�

1,�

1,�

2-b

lock

er

(27)

HH

3�,4

�-di

OH

�1

f

(28)

CH

3O

H4�

-OH

�1-b

lock

er,

�-a

gon

ist

aA

gon

ist

acti

vity

unle

ssin

dica

ted

oth

erw

ise.

bIn

dire

ctac

tivi

tyth

roug

hre

leas

eof

nor

epin

eph

rin

ean

dre

upta

kein

hib

itio

n.

c Pro

drug

.dM

ixed

dire

ctan

din

dire

ctac

tivi

ty.

e Nor

epin

eph

rin

ebi

osyn

thes

isin

hib

itor

.f N

etsu

mof

effe

cts

ofen

anti

omer

s.

7

Table 1.3 Imidazolines and Guanidines (Structures 29–41)

Compound Structure Receptor Activity

(29) �1-agonist

(30) �1-agonist

(31) �1-agonist

(32) �1-agonist

(33) �2-agonist

(34) �2-agonist

(35) �2-agonist

(36) �2-agonist


tic application; for example, �-blockers, �1-blockers, and �2-agonists are all employed totreat hypertension.

2.1.1 Applications of General AdrenergicAgonists. The mixed �- and �-agonist norepi-nephrine (1) has limited clinical applicationbecause of the nonselective nature of its actionin stimulating the entire adrenergic system.In addition to nonselective activity, it is orallyinactive because of rapid first-pass metabo-lism of the catechol hydroxyls by catechol-O-methyl-transferase (COMT) and must be ad-ministered intravenously. Rapid metabolismlimits its duration of action to only 1 or 2 min,even when given by infusion. Because its �-ac-tivity constricts blood vessels and thereby

raises blood pressure, (1) is used to counteractvarious hypotensive crises and as an adjuncttreatment in cardiac arrest where its �-activ-ity stimulates the heart. Although it also lacksoral activity because it is a catechol, epineph-rine (2) is far more widely used clinically than(1). Epinephrine, like norepinephrine, is usedto treat hypotensive crises and, because of itsgreater �-activity, is used to stimulate theheart in cardiac arrest. When administered in-travenously or by inhalation, epinephrine’s�2-activity makes it useful in relieving bron-choconstriction in asthma. Because it has sig-nificant �-activity, epinephrine is also used intopical nasal decongestants. Constriction ofdilated blood vessels by �-agonists in mucousmembranes shrinks the membranes and re-

Table 1.3 (Continued)

Compound Structure Receptor Activity

(37) �2-agonist

(38) naa

(39) naa

(40) �1-antagonist


aInhibit release of norepinephrine.

2 Clinical Applications 9

duces nasal congestion. Dipivefrin (4) is a pro-drug form of (2), in which the catechol hy-droxyls are esterified with pivalic acid.Dipivefrin is used to treat open-angle glau-coma through topical application to the eyewhere the drug (4) is hydrolyzed to epineph-rine (2), which stimulates both �- and �-recep-tors, resulting in both decreased productionand increased outflow of aqueous humor,which in turn lowers intraocular pressure.

Amphetamine (3) is orally active and,through an indirect mechanism, causes a gen-eral activation of the adrenergic nervous sys-tem. Unlike (1) and (2), amphetamine readilycrosses the blood-brain barrier to activate anumber of adrenergic pathways in the centralnervous system (CNS). Amphetamine’s CNSactivity is the basis of its clinical utility intreating attention-deficit disorder, narco-lepsy, and use as an anorexiant. These thera-peutic areas are treated elsewhere in thisvolume.

Ephedrine erythro-(5) and pseudoephed-rine threo-(5) are diastereomers with ephed-rine, a racemic mixture of the R,S and S,Rstereoisomers, and pseudoephedrine, a race-

mic mixture of R,R and S,S stereoisomers.Ephedrine is a natural product isolated fromseveral species of ephedra plants, which wereused for centuries in folk medicines in a vari-ety of cultures worldwide (9). Ephedrine hasboth direct activity on adrenoceptors and indi-rect activity, through causing release of nor-epinephrine from adrenergic nerve terminals.Ephedrine is widely used as a nonprescriptionbronchodilator. It has also been used as a va-sopressor and cardiac stimulant. Lacking phe-nolic hydroxyls, ephedrine crosses the blood-brain barrier far better than does epinephrine.Because of its ability to penetrate the CNS,ephedrine has been used as a stimulant andexhibits side effects related to its action in thebrain such as insomnia, irritability, and anxi-ety. It suppresses appetite and in high dosescan cause euphoria or even hallucinations. Inthe United States the purified chemical ephed-rine is considered a drug and regulated by theFDA. However, the dried plant material mahuang is considered by law to be a dietary sup-plement, and not subject to FDA regulation.As a result there are a large number of mahuang-containing herbal remedies and “nu-

Table 1.4 Quinazolines (Structures 42–44)

Compound R Receptor Activity





Table 1.5 Aryloxypropanolamines (Structures 45–59)

Compound ARYL R Receptor Selectivitya

(45) CH(CH3)2 �1

(46) CH(CH3)2 �1

(47) CH(CH3)2 �1

(48) CH(CH3)2 �1

(49) C(CH3)3 �1, �2

(50) CH(CH3)2 �1

(51) C(CH3)3 �1, �2

(52) CH(CH3)2 �1, �2

(53) CH(CH3)2 �1

(54) C(CH3)3 �1, �2


triceuticals” on the market whose active in-gredient is the adrenergic agonist ephedrine.Pseudoephedrine, the threo diastereomer, hasvirtually no direct activity on adrenergic re-ceptors but acts by causing the release of nor-epinephrine from nerve terminals, which inturn constricts blood vessels. Although it toocrosses the blood-brain barrier, pseudoephed-rine’s lack of direct activity affords fewer CNSside effects than does ephedrine. Pseudo-ephedrine is widely used as a nasal deconges-tant and is an ingredient in many nonprescrip-tion cold remedies.

Mephentermine (6) is another general ad-renergic agonist with both direct and indirectactivity. Mephentermine’s therapeutic utilityis as a parenteral vasopressor used to treathypotension induced by spinal anesthesia orother drugs.

2.1.2 Applications of �1-Agonists. All se-lective �1-agonists are vasoconstrictors, whichis the basis of their therapeutic activity. Thesole use of levonordefrin (7) is in formulationswith parenteral local anesthetics employed indentistry. Vasoconstriction induced by the�-agonist activity of (7) helps retain the localanesthetic near the site of injection and pro-longs the duration of anesthetic activity. Met-araminol (8) and methoxamine (9) are bothparenteral vasopressors selective for �-recep-tors and so have few cardiac stimulatory prop-erties. Because they are not substrates forCOMT, their duration of action is significantlylonger than that of norepinephrine, but theirprimary use is limited to treating hypotensionduring surgery or shock. Methoxamine is alsoused in treating supraventricular tachycardia.Midodrine (10) is an orally active glycine-

Table 1.5 (Continued)

Compound ARYL R Receptor Selectivitya

(55) C(CH3)3 �1, �2

(56) CH(CH3)2 �1, �2

(57) CH(CH3)2 �1, �2

(58) C(CH3)3 �1, �2

(59) �1, �1, �2

aAntagonists.


amide prodrug, hydrolyzed in vivo to (63), ananalog of methoxamine, and a vasoconstrictor.Midodrine is used to treat orthostatic hypo-tension.

Phenylephrine (11), also a selective �-ago-nist, may be administered parenterally for

severe hypotension or shock but is muchmore widely employed as a nonprescriptionnasal decongestant in both oral and topicalpreparations.

The imidazolines naphazoline (29), oxy-metazoline (30), tetrahydozoline (31), and xy-lometazoline (32) are all selective �1-agonists,widely employed as vasoconstrictors in topicalnonprescription drugs for treating nasal con-gestion or bloodshot eyes. Naphazoline andoxymetazoline are employed in both nasal de-congestants and ophthalmic preparations,whereas tetrahydrozoline is currently mar-keted only for ophthalmic use and xylometa-zoline only as a nasal decongestant.

2.1.3 Applications of �2-Agonists. Amino-imidazolines apraclonidine (33) and bri-monidine (34) are selective �2-agonists em-ployed topically in the treatment of glaucoma.Stimulation of �2-receptors in the eye reducesproduction of aqueous humor and enhancesoutflow of aqueous humor, thus reducing in-traocular pressure. Brimonidine is substan-tially more selective for �2-receptors over �1-

Table 1.6 Miscellaneous Adrenergic/Antiadrenergics (Structures 60–62)

Compound Structure Pharmacological Activity

(60) Antiadrenergic

(61) �-Antagonist

(62) �-Antagonist


receptors than is apraclonidine. Although bothare applied topically to the eye, measurablequantities of these drugs are detectable inplasma, so caution must be employed whenthe patient is also taking cardiovascularagents. Structurally related aminoimidazolineclonidine (35) is a selective �2-agonist takenorally for treatment of hypertension. The anti-hypertensive actions of clonidine are mediatedthrough stimulation of �2-adrenoceptorswithin the CNS, resulting in an overall decreasein peripheral sympathetic tone. Guanabenz (36)and guanfacine (37) are ring-opened analogs of(35), acting by the same mechanism and em-ployed as centrally acting antihypertensives.

Methyldopa (12) is another antihyperten-sive agent acting as an �2-agonist in the CNSthrough its metabolite, �-methyl-norepineph-rine (65). Methyldopa [the drug is the L-(S)-stereoisomer] is decarboxylated to �-methyl-dopamine (64) followed by stereospecific�-hydroxylation to the (1R,2S) stereoisomerof �-methylnorepinephrine (65). This stereo-isomer is an �2-agonist that, like clonidine,guanabenz, and guanfacine, causes a decreasein sympathetic output from the CNS.

2.1.4 Applications of �-Agonists. Most ofthe �-selective adrenergic agonists, albuterol(13; salbutamol in Europe), bitolterol (14),

formoterol (15), isoetharine (16), isoprotere-nol (17), levalbuterol [R-(�)-(13)], metapro-terenol (18), pirbuterol (19), salmeterol (21),and terbutaline (22) are used primarily asbronchodilators in asthma and other constric-tive pulmonary conditions. Isoproterenol (17)is a general �-agonist, and the cardiac stimu-lation caused by its �1-activity and its lack oforal activity attributed to first-pass metabo-lism of the catechol ring have led to dimin-ished use in favor of selective �2-agonists.Noncatechol-selective �2-agonists, such as al-buterol (13), metaproterenol (18), and ter-butaline (22), are available in oral dosageforms as well as in inhalers. All have similaractivities and durations of action. Pirbuterol(19) is an analog of albuterol, in which thebenzene ring has been replaced by a pyridinering. Similar to albuterol, (19) is a selective�2-agonist, currently available only for admin-istration by inhalation. Bitolterol (14) is a pro-drug, in which the catechol hydroxyl groupshave been converted to 4-methylbenzoic acidesters, providing increased lipid solubility andprolonged duration of action. Bitolterol is ad-ministered by inhalation, and the ester groupsare hydrolyzed by esterases to liberate the ac-tive catechol drug (66), which is subject to me-tabolism by COMT, although the duration ofaction of a single dose of the prodrug is up to8 h, permitting less frequent administrationand greater convenience to the patient. Morerecently developed selective �2-agonist bron-chodilators are formoterol (15) and salmeterol(21), which have durations of action of 12 h ormore. Terbutaline (22), in addition to its useas a bronchodilator, has also been used forhalting the contractions of premature labor.Ritodrine (20) is a selective �2-agonist that isused exclusively for relaxing uterine muscleand inhibiting the contractions of prematurelabor.

2.1.5 Applications of Antiadrenergics. Gua-nadrel (38) and guanethidine (39) are orallyactive antihypertensives, which are taken upinto adrenergic neurons, where they bind tothe storage vesicles and prevent release ofneurotransmitter in response to a neuronalimpulse, which results in generalized decreasein sympathetic tone. These drugs are availablebut seldom used.


Reserpine (60) is an old and historically im-portant drug that affects the storage and re-lease of norepinephrine. Reserpine is one ofseveral indole alkaloids isolated from the rootsof Rauwolfia serpentina, a plant whose rootswere used in India for centuries as a remedyfor snakebites and as a sedative. Reserpineacts to deplete the adrenergic neurons of theirstores of norepinephrine by inhibiting the ac-tive transport Mg-ATPase responsible for se-questering norepinephrine and dopaminewithin the storage vesicles. Monoamine oxi-dase (MAO) destroys the norepinephrine anddopamine that are not sequestered in vesicles.As a result the storage vesicles contain littleneurotransmitter; adrenergic transmission isdramatically inhibited; and sympathetic toneis decreased, thus leading to vasodilation.Agents with fewer side effects have largely re-placed reserpine in clinical use.

Metyrosine (23, �-methyl-L-tyrosine), anorepinephrine biosynthesis inhibitor, is inlimited clinical use to help control hyperten-sive episodes and other symptoms of catechol-amine overproduction in patients with therare adrenal tumor pheochromocytoma (10).Metyrosine, a competitive inhibitor of ty-rosine hydroxylase, inhibits the production ofcatecholamines by the tumor. Although mety-rosine is useful in treating hypertensioncaused by excess catecholamine biosynthesis

in pheochromocytoma tumors, it is not usefulfor treating essential hypertension.

2.1.6 Applications of Nonselective �-An-tagonists. Because antagonism of �1-adreno-ceptors in the peripheral vascular smoothmuscle leads to vasodilation and a decrease inblood pressure attributed to a lowering of pe-ripheral resistance, alpha-blockers have beenemployed as antihypertensives for decades.However, nonselective �-blockers such as phe-noxybenzamine (62), phentolamine (40), andtolazoline can also increase sympathetic out-put through blockade of inhibitory presynap-tic �2-adrenoceptors, resulting in an increasein circulating norepinephrine, which causesreflex tachycardia. Thus the use of theseagents in treating most forms of hypertensionhas been discontinued and replaced by use ofselective �1-antagonists discussed below. Cur-rent clinical use of the nonselective agents(40), (41), and (62) is primarily treatment ofhypertension induced by pheochromocytoma,a tumor of the adrenal medulla, which se-cretes large amounts of epinephrine and nor-epinephrine into the circulation. Dapiprazole(61) is an ophthalmic nonselective �-antago-nist applied topically to reverse mydriasis in-duced by other drugs and is not used to treathypertension.

2.1.7 Applications of Selective �1-Antago-nists. Quinazoline-selective �1-blockers dox-azosin (42), prazosin (43), and terazosin (44)have replaced the nonselective �-antagonistsin clinical use as antihypertensives. Their abil-ity to dilate peripheral vasculature has alsomade these drugs useful in treating Raynaud’ssyndrome. The �1-selective agents have a fa-vorable effect on lipid profiles and decreaselow density lipoproteins (LDL) and triglycer-ides, and increase high density lipoproteins(HDL).

Contraction of the smooth muscle of theprostate gland, prostatic urethra, and bladderneck is also mediated by �1-adrenoceptors,with �1A being predominant, and blockade ofthese receptors relaxes the tissue. For this rea-son the quinazoline �1-antagonists doxazosin(42), prazosin (43), and terazosin (44) havealso found use in treatment of benign pros-tatic hyperplasia (BPH). However, prazosin,


doxazosin, and terazosin show no significantselectivity for any of the three known �1-adre-noceptor subtypes, �1A, �1B, and �1D (11). Thestructurally unrelated phenylethylamine �1-antagonist tamsulosin (24) is many fold moreselective for �1A-receptors than for the other�1-adrencoceptors. Tamsulosin is employedonly for treatment of BPH, given that it haslittle effect on the �1B- and �1D-adrenoceptors,which predominate in the vascular bed (12)and have little effect on blood pressure (13).

2.1.8 Applications of �-Antagonists. �-An-tagonists are among the most widely employedantihypertensives and are also considered thefirst-line treatment for glaucoma. There are16 �-blockers listed in Table 1.1 and 15 ofthem are in the chemical class of aryloxypro-panolamines. Only sotalol (25) is a phenyleth-ylamine. Acebutolol (45), atenolol (46), biso-prolol (48), metoprolol (53), nadolol (54),penbutolol (55), pindolol (56), and proprano-lol (57) are used to treat hypertension but notglaucoma. Betaxolol (47), carteolol (49), andtimolol (58) are used both systemically to treathypertension and topically to treat glaucoma.Levobetaxolol [S-(�)-(47)], levobunolol (51),and metipranolol (52) are employed only intreating glaucoma. Betaxolol (racemic 47) isavailable in both oral and ophthalmic dosageforms for treating hypertension and glau-coma, respectively, but levobetaxolol, the en-antiomerically pure S-(�)-stereoisomer is cur-rently available only in an ophthalmic dosageform. Esmolol (50) is a very short acting�-blocker administered intravenously foracute control of hypertension or certain su-praventricular arrhythmias during surgery.Sotalol (25) is a nonselective �-blocker used totreat ventricular and supraventricular ar-rhythmias not employed as an antihyperten-sive or antiglaucoma agent. �-Antagonistsmust be used with caution in patients withasthma and other reactive pulmonary diseasesbecause blockade of �2-adrenoceptors may ex-acerbate the lung condition. Even the agentslisted as being �1-selective have some level of�2-blocking activity at higher therapeuticdoses. Betaxolol is the most �1-selective of thecurrently available agents.

2.1.9 Applications of �/�-Antagonists. Car-vedilol (59), an aryloxypropanolamine, hasboth �- and �-antagonist properties and isused both as an antihypertensive and to treatcardiac failure. Both enantiomers have selec-tive �1-antagonist properties but most of the�-antagonism is attributable to the S-(�) iso-mer. Labetalol (26) is also an antihypertensivewith both selective �1-antagonist propertiesand nonselective �-antagonism. Labetalol isan older drug than carvedilol and is not aspotent as carvedilol, particularly as a �-antag-onist.

2.1.10 Applications of Agonists/Antago-nists. Dobutamine (27) is a positive inotropicagent administered intravenously for conges-tive heart failure. The (�)-isomer has both �and � agonist effects, whereas the (�)-isomeris an �-antagonist but a �-agonist like the en-antiomer. The �-stimulatory effects predomi-nate as the �-effects cancel. As a catechol ithas no oral activity and even given intrave-nously has a half-life of only 2 min. Isoxsu-prine (28) is an agent with �-antagonist and�-agonist properties, which has been used forperipheral and cerebral vascular insufficiencyand for inhibition of premature labor. Isoxsu-prine is seldom used any more.

2.2 Absorption, Distribution, Metabolism,and Elimination

Because of the large numbers of chemicals act-ing as either adrenergics or adrenergic-block-ing drugs, only representative examples willbe given and limited to metabolites identifiedin humans. Because drugs with similar struc-tures are often metabolized by similar routes,the examples chosen are representative ofeach structural class. Although it contains nostructural details of metabolic pathways,Drug Facts and Comparisons (14) is an out-standing comprehensive compilation of phar-macokinetic parameters such as absorption,duration of action, and routes of eliminationfor drugs approved by the FDA for use in theUnited States.

2.2.1 Metabolism of Representative Phenyl-ethylamines. Norepinephrine (1) and epi-nephrine (2) are both substrates for MAO,


which oxidatively deaminates the side chain ofeither to form the same product DOPGAL(67), and for catechol-O-methyltransferase(COMT), which methylates the 3�-phenolicOH of each to form (68). Metabolite (68) issubsequently oxidized by MAO to form alde-hyde (69), and aldehyde (68) may be methyl-ated by COMT to also form (69). This alde-hyde may then be either oxidized by aldehydedehydrogenase (AD) to (70) or reduced by al-dehyde reductase to alcohol (71). Alternateroutes to (70) and (71) from (67) are alsoshown. Several of these metabolites are ex-creted in the urine as sulfate and glucuronideconjugates (15). As previously mentioned, nei-ther (1) nor (2) is orally active because of ex-tensive first-pass metabolism by COMT, andboth have short durations of action because ofrapid metabolic deactivation by the routes

shown. Any catechol-containing drug will alsolikely be subject to metabolism by COMT.

Ephedrine (5), a close structural analog of(2), having no substituents on the phenyl ring,is well absorbed after an oral dose and overhalf the dose is eliminated unchanged in theurine. The remainder of the dose is largelydesmethylephedrine (72), deamination prod-uct (73), and small amounts of benzoic acidand its conjugates (16). No aromatic ring-hy-droxylation products were detected. This is inmarked contrast to the case with amphet-amine (3), in which ring-hydroxylated prod-ucts are major metabolites.

Albuterol (13) is not subject to metabolismby COMT and is orally active but does have a4�- OH group subject to conjugation. The ma-jor metabolite of albuterol (13) is the 4�-O-sulfate (74) (17). The sulfation reaction is ste-


reoselective for the active R-(�)-isomer (18–20), resulting in higher plasma levels of theless active S-(�)-isomer after oral administra-tion or swallowing of inhaled dosages.

Tamsulosin (24) is metabolized by CYP3A4to both the phenolic oxidation product (75)and deaminated metabolite (76) and their con-jugation products (21–23). The other productsgenerated from the remainder of the drugmolecule during formation of (76) were notexplicitly identified. Tamsulosin is well ab-sorbed orally and extensively metabolized.Less than 10% excreted unchanged in urine.

2.2.2 Metabolism of Representative Imida-zolines and Guanidines. In humans, clonidine(35) is excreted about 50% unchanged in the

urine and the remainder oxidized by the liveron both the phenyl ring and imidazoline ringto (77), (78), and (79). Oxidation of the imida-zoline ring presumably leads to the ring-opened derivatives (80) and (81). All metabo-lites are inactive but do not appear to befurther conjugated.

In contrast, less than 2% of guanabenz(36), a ring-opened analog of (35), is excretedunchanged in the urine (24). The major me-tabolite (35%) is the 4-hydroxylated com-pound (82) and its conjugates, whereas guana-benz-N-glucuronide accounts for about 6%.Also identified were 2,6-dichlorobenzyl alco-hol (83) (as conjugates) and the Z-isomer of


guanabenz. About 15 other trace metaboliteswere detected by chromatography but notidentified.

2.2.3 Metabolism of Representative Quina-zolines. Terazosin (46) is completely absorbed,

with little or no first-pass metabolism, andabout 38% of administered terazosin is elimi-nated unchanged in urine and feces. The re-mainder is metabolized by hydrolysis of theamide bond to afford (84) and by O-demethyl-ation to form the 6- and 7-O-demethyl metab-olites (85) and (86), respectively (25). Diamine(87) has also been identified as a minor metab-olite of terazosin, probably arising from oxida-tion and hydrolysis of the piperazine ring, al-though the intermediate products have notbeen identified.

Doxazosin (42) is well absorbed, with 60%bioavailability, but only about 5% is ex-creted unchanged. The major routes of me-tabolism are, like terazosin, 6- and 7-O-demethylation to afford (88) and (89),respectively (26). Hydroxylation at 6� and 7�,to form (90) and (91), forms the other twoidentified metabolites.

2.2.4 Metabolism of Representative Aryl-oxypropanolamines. Propranolol (57), thefirst successful �-blocker, is also the most li-pophilic, with an octanol/water partition coef-ficient of 20.2 (27), and is extensively metabo-lized. At least 20 metabolites of propranololhave been demonstrated (28), only a few ofwhich are shown. The 4�-hydroxy metabolite(92) is equipotent with the parent compound(29). CYP2D6 is responsible for the 4�-hy-droxylation and CYP1A2 for oxidative re-moval of the isopropyl group from the nitro-gen to form (93) (30). The metabolites as wellas the parent drug are extensively conjugated



as sulfates and glucuronides. The high lipophi-licity of propranolol provides ready passageacross the blood-brain barrier and leads to thesignificant CNS effects of propranolol (27).

On the other hand, atenolol (46), with anoctanol/buffer partition coefficient of 0.02(27), does not cross the blood-brain barrier toany significant extent and is eliminated al-most entirely as the unchanged parent drug inthe urine and feces. Very small amounts ofhydroxylated metabolite (94) and its conju-gates have been identified (31), but well over90% of atenolol is eliminated unchanged.

Metoprolol (53) is cleared principally by he-patic metabolism and is only 50% bioavailablebecause of extensive first-pass metabolism.The major metabolite (65%) is the carboxylicacid (95), produced by CYP2D6 O-demethyl-ation followed by further oxidation (32–34).Benzylic oxidation CYP2D6 forms an activemetabolite (96), which retains beta-blockingactivity (35). The N-dealkylated product is aminor metabolite.

3 PHYSIOLOGY AND PHARMACOLOGY

The physiology and pharmacology of adrener-gic and adrenergic-blocking drugs are wellcovered in standard pharmacology textbooks(36, 37).

3.1 Physiological Significance

Adrenergic and adrenergic-blocking drugs acton effector cells through receptors that are

normally activated by the neurotransmitternorepinephrine (1, noradrenaline), or theymay act on the neurons that release the neu-rotransmitter. The term adrenergic stemsfrom the discovery early in the twentieth cen-tury that administration of the adrenal med-ullar hormone adrenaline (epinephrine) hadspecific effects on selected organs and tissuessimilar to the effects produced by stimulationof the sympathetic nervous system, which was

3 Physiology and Pharmacology 21

originally defined anatomically (38). Todaythe terms adrenergic nervous system and sym-pathetic nervous system are generally used in-terchangeably. The sympathetic nervous sys-tem is a division of the autonomic nervoussystem, which innervates organs such as theheart, lungs, blood vessels, glands, and smoothmuscle in various tissues and regulates func-tions not normally under voluntary control.The effects of the sympathetic stimulation ona few organs and tissues of particular rele-vance to current pharmaceutical interven-tions are shown in Table 1.7 (39, 40). Excellentoverviews of the adrenergic nervous systemand its role in control of human physiology areprovided in Katzung (39) and Hoffman andPalmer (40).

3.2 Biosynthesis, Storage, and Releaseof Norepinephrine

Biosynthesis of norepinephrine takes placewithin adrenergic neurons near the terminus

of the axon near the junction with the effectorcell. The amino acid L-tyrosine (97) is activelytransported into the neuron cell (41), wherethe cytoplasmic enzyme tyrosine hydroxylase(tyrosine-3-monooxygenase) oxidizes the 3�-position to form the catechol-amino-acid L-dopa (98) in the rate-limiting step in norepi-nephrine biosynthesis (42). L-Dopa isdecarboxylated to dopamine (99) by aromatic-L-amino acid decarboxylase, another cytoplas-mic enzyme. Aromatic-L-amino acid decarboxyl-ase is more commonly known as dopadecarboxylase. Dopamine is then taken up byactive transport into storage vesicles or granuleslocated near the terminus of the adrenergic neu-ron. Within these vesicles, the enzyme dopa-mine �-hydroxylase stereospecifically intro-duces a hydroxyl group in the R absoluteconfiguration on the carbon atom beta to theamino group to generate the neurotransmitternorepinephrine (1). Norepinephrine is stored inthe vesicles in a 4:1 complex, with adenosine


triphosphate (ATP) in such quantities that eachvesicle in a peripheral adrenergic neuron con-tains between 6000 and 15,000 molecules of nor-epinephrine (43). The pathway for epinephrine(2) biosynthesis in the adrenal medulla is thesame, with the additional step of conversion of(1) to (2) by phenylethanolamine-N-methyl-transferase.

Norepinephrine remains in the vesicles un-til it is released into the synapse during signaltransduction. A wave of depolarization reach-ing the terminus of an adrenergic neuron trig-gers the transient opening of voltage-depen-dent calcium channels, causing an influx ofcalcium ions. This influx of calcium ions trig-gers fusion of the storage vesicles with theneuronal cell membrane, spilling the norepi-nephrine and other contents of the vesiclesinto the synapse through exocytosis. A sum-mary view of the events involved in norepi-

nephrine biosynthesis, release, and fate isgiven in Fig. 1.1. After release, norepinephrinediffuses through the intercellular space tobind reversibly to adrenergic receptors (alphaor beta) on the effector cell, triggering a bio-chemical cascade that results in a physiologicresponse by the effector cell. In addition to thereceptors on effector cells, there are also adre-noreceptors that respond to norepinephrine(�2-receptors) or epinephrine (�2-receptors)on the presynaptic neuron, which modulatethe release of additional neurotransmitterinto the synapse. Activation of presynaptic �2-adrenoceptors by (1) inhibits the release of ad-ditional (1), whereas stimulation of presynap-tic �2-adrenoceptors by (2) enhances therelease of (1), thus increasing overall sympa-thetic activation. Removal of norepinephrinefrom the synapse is accomplished by twomechanisms, reuptake and metabolism, to in-

Table 1.7 Selected Tissue Response to Adrenergic Stimulation

Tissue Principal Adrenergic Receptor Effect

Heart �1 (minor �2, �3) Increased rate and forceBlood vessels

Skin, mucosa, visera �1 ConstrictionSkeletal muscle �2 DilationRenal �1 Constriction

Lungs (bronchial muscle) �2 RelaxationEye

Radial muscle, iris �1 Contraction (pupilary dilation)Ciliary muscle �2 Relaxation

Uterus (pregnant) �2 RelaxationLiver �1, �2 Glycogenolysis, gluconeogenesisFat cells �3 LipolysisKidney

Renin release �1 Increased renin secretionminor �1 Decreased renin secretion


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24

active compounds. The most important ofthese mechanisms is transmitter recyclingthrough active transport uptake into the pre-synaptic neuron. This process, called up-take-1, is efficient and, in some tissues, up to95% of released norepinephrine is removedfrom the synapse by this mechanism (44). Partof the norepinephrine taken into the presyn-aptic neuron by uptake-1 is metabolized byMAO through the same processes discussedearlier under norepinephrine metabolism, butmost is sequestered in the storage vesicles tobe used again as neurotransmitter. This up-take mechanism is not specific for (1) and anumber of drugs are substrates for the uptakemechanism and others inhibit reuptake, lead-ing to increased adrenergic stimulation. A lessefficient uptake process, uptake-2, operates ina variety of other cell types but only in thepresence of high concentrations of norepi-nephrine. That portion of released norepi-nephrine that escapes uptake-1 diffuses out ofthe synapse and is metabolized in extraneuro-nal sites by COMT. MAO present at extraneu-ronal sites, principally the liver and bloodplatelets, also metabolizes norepinephrine.

3.3 Effector Mechanismsof Adrenergic Receptors

Adrenoceptors are proteins embedded in thecell membrane that are coupled through a G-protein to effector mechanisms that translateconformational changes caused by activationof the receptor into a biochemical event withinthe cell. All of the �-adrenoceptors are coupledthrough specific G-proteins (Gs) to the activa-tion of adenylyl cyclase (45). When the recep-tor is stimulated by an agonist, adenylyl cy-clase is activated to catalyze conversion ofATP to cyclic-adenosine monophosphate(cAMP), which diffuses through the cell for atleast short distances to modulate biochemicalevents remote from the synaptic cleft. Modu-lation of biochemical events by cAMP includesa phosphorylation cascade of other proteins.cAMP is rapidly deactivated by hydrolysis ofthe phosphodiester bond by the enzyme phos-phodiesterase. The �2-receptor may use morethan one effector system, depending on thelocation of the receptor; however, to date thebest understood effector system of the �2-re-ceptor appears to be similar to that of the �-re-

ceptors, except that linkage through a G-pro-tein (Gi) leads to inhibition of adenylyl cyclaseinstead of activation.

The �1-adrenoreceptor, on the other hand,is linked through yet another G-protein to acomplex series of events involving hydrolysisof polyphosphatidylinositol (46). The firstevent set in motion by activation of the �1-receptor is activation of the enzyme phospho-lipase C, which catalyzes the hydrolysis ofphosphatidylinositol-4,5-biphosphate (PIP2).This hydrolysis yields two products, each ofwhich has biologic activity as second messen-gers of the �1-receptor. These are 1,2-diacyl-glycerol (DAG) and inositol-1,4,5-triphos-phate (IP3). IP3 causes the release of calciumions from intracellular storage sites in the en-doplasmic reticulum, resulting in an increasein free intracellular calcium levels. Increasedfree intracellular calcium is correlated withsmooth muscle contraction. DAG activates cy-tosolic protein kinase C, which may induceslowly developing contractions of vascularsmooth muscle. The end result of a complexseries of protein interactions triggered by ag-onist binding to the �1-adrenoceptor includesincreased intracellular free calcium, whichleads to smooth muscle contraction. Becausesmooth muscles of the wall of the peripheralvascular bed are innervated by �1-receptors,stimulation leads to vascular constriction andan increase in blood pressure.

3.4 Characterization of AdrenergicReceptor Subtypes

The discovery of subclasses of adrenergic re-ceptors and the ability of relatively small mol-ecule drugs to stimulate differentially or blockthese receptors represented a major advancein several areas of pharmacotherapeutics. Anexcellent review of the development of adreno-ceptor classifications is available in Hiebel etal. (47).

The adrenoceptors, both alpha and beta,are members of a receptor superfamily ofmembrane-spanning proteins, including mus-carine, serotonin, and dopamine receptors,that are coupled to intracellular GTP-bindingproteins (G-proteins), which determine thecellular response to receptor activation (48).All G-protein–coupled receptors exhibit acommon motif of a single polypeptide chain


that is looped back and forth through the cellmembrane seven times, with an extracellularN-terminus and intracellular C-terminus.One of the most thoroughly studied of thesereceptors is the human �2-adrenoreceptor(49). The seven transmembrane domains,TMD1-TMD7, are composed primarily of li-pophilic amino acids arranged in �-helicesconnected by regions of hydrophilic amino ac-ids. The hydrophilic regions form loops on theintracellular and extracellular faces of themembrane. In all of the adrenoceptors the ag-onist/antagonist recognition site is locatedwithin the membrane-bound portion of the re-ceptor. This binding site is within a pocketformed by the membrane-spanning regions ofthe peptide. All of the adrenoceptors are cou-pled to their G-protein through reversiblebinding interactions with the third intracellu-lar loop of the receptor protein.

Binding studies with selectively mutated�2-receptors have provided strong evidencefor binding interactions between agonist func-tional groups and specific residues in thetransmembrane domains of adrenoceptors(50–52). Such studies indicate that Asp113 intransmembrane domain 3 (TMD3) of the �2-receptor is the acidic residue that forms abond, presumably ionic or a salt bridge, withthe positively charged amino group of cate-cholamine agonists. An aspartic acid residue isalso found in a comparable position in all ofthe other adrenoceptors as well as otherknown G-protein–coupled receptors that bindsubstrates having positively charged nitro-gens in their structures. Elegant studies withmutated receptors and analogs of isoprotere-nol demonstrated that Ser204 and Ser207 ofTMD5 are the residues that form hydrogenbonds with the catechol hydroxyls of �2-ago-nists. Furthermore, the evidence indicatesthat Ser204 interacts with the meta hydroxylgroup of the ligand, whereas Ser207 interactsspecifically with the para hydroxyl group.Serine residues are found in corresponding po-sitions in the fifth transmembrane domain ofthe other known adrenoceptors. Evidence in-dicates that the phenylalanine residue ofTMD6 is also involved in ligand-receptorbonding with the catechol ring. Structural dif-ferences exist among the various adrenocep-tors with regard to their primary structure,

including the actual peptide sequence andlength. Each of the adrenoceptors is encodedon a distinct gene, and this information wasconsidered crucial to the proof that each adre-noreceptor is indeed distinct, although re-lated. The amino acids that make up the seventransmembrane regions are highly conservedamong the various adrenoreceptors, but thehydrophilic portions are quite variable. Thelargest differences occur in the third intracel-lular loop connecting TMD5 and TMD6, whichis the site of linkage between the receptor andits associated G-protein. Sequences and bind-ing specificities have been reported for numer-ous �- and �-adrenoceptor subtypes (47, 53–56). For purposes of drug design andtherapeutic targeting, the most critical recep-tors are the �1A on prostate smooth muscle,�1B on vascular smooth muscle and in the kid-ney, �2 in the CNS, �1 in heart, �2 in bronchialsmooth muscle, and �3 in adipose tissue.

4 HISTORY

In 1895 Oliver and Schafer reported (57) thatadrenal gland extracts caused vasoconstric-tion and dramatic increases in blood pressure.Shortly thereafter various preparations ofcrude adrenal extracts were being marketedlargely to staunch bleeding from cuts andabrasions. In 1899 Abel reported (58) isolationof a partially purified sample of the active con-stituent (2), which he named epinephrine.Shortly thereafter von Furth (59) employed analternative procedure to isolate another im-pure sample of (2), which he named suprare-nin, claiming it to be a different substancethan that isolated by Abel. The pure hormone(2) was finally obtained in 1901 by both Taka-mine (60) and Aldrich (61). Takamine gave (2)yet a third name, adrenalin. Although thechemical structure was still not definitivelyknown, a pure preparation of (2) was firstmarketed by Parke, Davis & Co. under thetrade name Adrenaline (62, 63). Adrenalineeventually became the generic name employedoutside the United States, whereas epineph-rine became the U.S. approved name. By 1903Pauly (64) had demonstrated that “adrena-line” was levorotatory and proposed two pos-sible structures consistent with the available


data. The structure of racemic (2) was conclu-sively proved through nearly simultaneoussynthesis by Stolz at Farbwerke Hoechst (65)and Dakin at the University of Leeds (66), butit had only one half the activity of the naturallevorotatory isomer (67). The racemate wasresolved by Flächer in 1908 (68).

The earliest major clinical application of (2)was the report in 1900 (69) of the utility ofinjected adrenal extracts in treating asthmaattacks, followed in 1903 by a report (70) of theuse of purified (2) for the same purpose. In-jected epinephrine rapidly became the stan-dard therapy for treatment of acute asthmaattacks. A nasal spray containing epinephrinewas available by 1911 and administrationthrough an inhaler was reported in 1929. Also,early in the 1900s Hoechst employed the vaso-constrictor properties of epinephrine to pro-long the duration of action of their newly de-veloped local anesthetic procaine (63).

It had been recognized early on (71) thatthere were similarities between the effects ofadministration adrenal gland extracts andstimulation of the sympathetic nervous sys-tem. Elliot (72) suggested that adrenalinemight be released by sympathetic nerve stim-ulation and over the years the term adrenergicnerves became effectively synonymous withsympathetic nerves. In 1910 Barger and Dale(73) reported a detailed structure-activity re-lationship study of epinephrine analogs andintroduced the term sympathomimetic forchemicals that mimicked the effects of sympa-thetic nerve stimulation, but they also notedsome important differences between the ef-fects of administered adrenaline and stimula-tion of sympathetic nerves. It was not until1946 that von Euler demonstrated that theactual neurotransmitter released at the termi-nus of sympathetic neurons was norepineph-rine (1) rather than epinephrine (2) (74). In1947 compound (17), the N-isopropyl analogof (1) and (2), was reported to possess bron-chodilating effects similar to those of (2) butlacking its dangerous pressor effects. In 1951(17) was introduced into clinical use as isopro-terenol (isoprenaline) and became the drug ofchoice for treating asthma for two decades.

In the 1950s, dichloroisoproterenol (DCI,100), a derivative of isoproterenol, in whichthe catechol hydroxyls had been replaced by

chlorines, was discovered to be a �-antagonistthat blocked the effects of sympathomimeticamines on bronchodilation, uterine relax-ation, and heart stimulation (75). AlthoughDCI had no clinical utility, replacement of the3,4-dichloro substituents with a carbon bridgeto form a naphthylethanolamine derivativedid afford a clinical candidate, pronethalol(101), introduced in 1962 only to be with-drawn in 1963 because of tumor induction inanimal tests.

Shortly thereafter, a major innovation wasintroduced when it was discovered that anoxymethylene bridge, OCH2, could be intro-duced into the arylethanolamine structure ofpronethalol to afford propranolol (57), an ary-loxypropanolamine and the first clinically suc-cessful �-blocker.

To clarify some of the puzzling differentialeffects of sympathomimetic drugs on varioustissues, in 1948 Ahlquist (76) introduced theconcept of two distinct types of adrenergic re-ceptors as defined by their responses to (1),(2), and (17), which he called alpha receptorsand beta receptors. Alpha receptors were de-fined as those that responded in rank order ofagonist potency as (2) � (1) �� (17). Beta re-ceptors were defined as those responding inpotency order of (17) � (2) � (1). Subse-quently, �-receptors were further divided into�1-receptors, located primarily in cardiac tis-sue, and �2-adrenoceptors, located in smoothmuscle and other tissues, given that (1) and(2) are approximately equipotent at cardiac

4 History 27

�-receptors, although (2) is 10 to 50 timesmore potent than (1) at most smooth muscle�-receptors (77). Alpha receptors were alsosubdivided into �1 (postsynaptic) and �2 (pre-synaptic) adrenoceptors (78). Development ofselective agonists and antagonists for thesevarious adrenoceptors has been thoroughly re-viewed in Ruffolo et al. (79).

5 STRUCTURE-ACTIVITY RELATIONSHIPS

Comprehensive reviews of the structure-activ-ity relationships (SAR) of agonists and antag-onists of �-adrenoceptors (80) and �-adreno-ceptors (81) are available, which thoroughlycover developments through the late 1980s.Only summaries of these structure-activity re-lationships are provided here.

5.1 Phenylethylamine Agonists

The structures of the phenylethylamine ad-renergic agonists were summarized in Table1.2. Agents of this type have been extensively

studied over the years since the discovery ofthe naturally occurring prototypes, epineph-rine and norepinephrine, and the structuralrequirements, and tolerances for substitu-tions at each of the indicated positions havebeen well established and reviewed (79, 82). Ingeneral, a primary or secondary aliphaticamine separated by two carbons from a substi-tuted benzene ring is minimally required forhigh agonist activity in this class. Tertiary orquaternary amines have little activity. Be-cause of the basic amino groups, pKa valuesrange from about 8.5 to 10, and all of theseagents are highly positively charged at physi-ologic pH. Most agents in this class have ahydroxyl group on C-1 of the side chain, � tothe amine, as in epinephrine and norepineph-rine. Given these features in common, the na-

ture of the other substituents determines re-ceptor selectivity and duration of action.

5.1.1 R1 Substitution on the Amino Nitrogen.As R1 is increased in size from hydrogen innorepinephrine to methyl in epinephrine toisopropyl in isoproterenol, activity at �-recep-tors decreases and activity at �-receptors in-creases. Activity at both �- and �-receptors ismaximal when R1 is methyl as in epinephrine,but �-agonist activity is dramatically de-creased when R1 is larger than methyl and isnegligible when R1 is isopropyl as in (17), leav-ing only �-activity. Presumably, the �-recep-tor has a large lipophilic binding pocket adja-cent to the amine-binding aspartic acidresidue, which is absent in the �-receptor. AsR1 becomes larger than butyl, affinity for �1-receptors returns, but not intrinsic activity,which means large lipophilic groups can affordcompounds with �1-blocking activity [e.g.,tamsulosin (24) and labetalol (26)]. Tamsulo-sin (24) is more selective for �1A, the �1-adre-noceptor subtype found in the prostate gland,over those found in vascular tissue. In addi-tion, the N-substituent can also provide selec-tivity for different �-receptors, with a t-butylgroup affording selectivity for �2-receptors.For example, with all other features of themolecules being constant, (66) [the activemetabolite of prodrug bitolterol (14)] is a se-lective �2-agonist, whereas (17) is a general�-agonist. When considering its use as a bron-chodilator, it must be recognized that a gen-eral �-agonist such as (17) has undesirablecardiac stimulatory properties (because of its�1-activity) that are greatly diminished in aselective �2-agonist.

5.1.2 R2 Substitution � to the Basic Nitro-gen, Carbon-2. Small alkyl groups, methyl orethyl, may be present on the carbon adjacentto the amino nitrogen. Such substitutionslows metabolism by MAO but has little over-all effect on duration of action of catechols be-cause they remain substrates for COMT. Re-sistance to MAO activity is more importantin noncatechol indirect-acting phenylethyl-amines. An ethyl group in this position dimin-ishes �-activity far more than �-activity, and ispresent in isoetharine (16). Substitution onthis carbon introduces an asymmetric center,


producing pairs of diastereomers when an OHgroup is present on C-1. These stereoisomerscan have significantly different biologic andchemical properties. For example, maximaldirect activity in the stereoisomers of �-meth-ylnorepinephrine resides in the erythro ste-reoisomer (65), with the (1R,2S) absolute con-figuration (83), which is the active metaboliteof the prodrug methyldopa (12) (84). The con-figuration of C-2 has a great influence on re-ceptor binding because the (1R,2R) diaste-reomer of �-methylnorepinephrine hasprimarily indirect activity, even though the ab-solute configuration of the hydroxyl-bearing C-1is the same as that in norepinephrine. Inaddition, with respect to �-activity, this addi-tional methyl group also makes the direct-acting(1R,2S) isomer of �-methylnorepinephrine se-lective for �2-adrenoceptors over �1-adrenocep-tors, affording the central antihypertensiveproperties of methyldopa.

5.1.3 R3 Substitution on Carbon-1. In thephenylethyamine series, a hydroxyl group atthis position in the R absolute configuration ispreferred for maximum direct agonist activityon both �- and �-adrenoceptors. If a hydroxylis present in the S absolute configuration, theactivity is generally the same as that of thecorresponding chemical with no substituent.This is the basis for the well-known Easson-Stedman hypothesis of three-point attachmentof phenylethanolamines to adrencoceptorsthrough stereospecific bonding interactionswith the basic amine, hydroxyl group, and ar-omatic substituents (85). A comprehesive andexcellent review of the stereochemistry of ad-renergic drug-receptor interactions was writ-ten by Ruffolo (86).

An example of a phenethylamine agonistlacking an OH group on C-1 is dobutamine(27), which has activity on both �- and �-re-ceptors but, because of some unusual proper-ties of the chiral center on R1, the bulky nitro-gen substituent, the overall pharmacologicresponse is that of a selective �1-agonist (87).The (�)-isomer of dobutamine is an �1-agonistand vasopressor. The (�)-isomer is an �1-antagonist; thus, when the racemate is usedclinically, the �-effects of the enantiomers ef-fectively cancel, leaving the �-effects to pre-dominate. The stereochemistry of the methyl

substituent does not affect the ability of thedrug to bind to the �1-receptor but does affectthe ability of the molecule to activate the re-ceptor; that is, the stereochemistry of themethyl group affects intrinsic activity but notaffinity. Because both stereoisomers are�-agonists, with the (�)-isomer about 10times as potent as the (�)-isomer, the net ef-fect is �-stimulation. Dobutamine is used as acardiac stimulant after surgery or congestiveheart failure. As a catechol, dobutamine isreadily metabolized by COMT and has a shortduration of action with no oral activity.

5.1.4 R4 Substitution on the AromaticRing. The natural 3�,4�-dihydroxy substitutedbenzene ring present in norepinephrine pro-vides excellent receptor activity for both �-and �-sites, but such catechol-containing com-pounds have poor oral bioavailability andshort durations of action, even when adminis-tered intravenously, because they are rapidlymetabolized by COMT. Alternative substitu-tions have been found that retain good activitybut are more resistant to COMT metabolism.For example, 3�,5�-dihydroxy compounds arenot good substrates for COMT and, in addi-tion, provide selectivity for �2-receptors.Thus, because of its ring-substitution pattern,metaproterenol (18) is an orally active bron-chodilator having little of the cardiac stimula-tory properties possessed by isoproterenol(17).

Other substitutions are possible that en-hance oral activity and provide selective �2-activity, such as the 3�-hydroxymethyl, 4�-hy-droxy substitution pattern of albuterol (13),which is also not a substrate for COMT. A re-cently developed selective �2-agonist with anextended duration of action is salmeterol (21),which has the same phenyl ring substitutionR4 as that of (13) but an unusually long andlipophilic group R1 on the nitrogen. The octa-nol/water partition coefficient log P for salme-terol is 3.88 vs. 0.66 for albuterol and the du-ration of action of salmeterol is 12 vs. 4 h foralbuterol (88). There is substantial evidencethat the extended duration of action is attrib-uted to a specific binding interaction of theextended lipophilic side chain with a specificregion of the �2-receptor, affording salmeterola unique binding mechanism (89). The long

5 Structure-Activity Relationships 29

lipophilic nitrogen substituent of salmeterolhas been shown, through a series of site-di-rected mutagenesis experiments, to bind to aspecific 10 amino acid region of transmem-brane domain 4 of the �2-adrenoceptor. Thisregion, amino acids 149–158, is located at theinterface of the cyctoplasm and TMD4. Thus“anchored” by the side chain, the remainingpart of the molecule can pivot and repetitivelystimulate the receptor through binding to as-partate 113 of TMD3 and serines 204/207 ofTMD5. This lipophilic anchoring is postulatedto keep the drug localized at the site of actionand produce the long duration of action ofsalmeterol.

At least one of the phenyl substituentsmust be capable of forming hydrogen bondsand, if there is only one, it should be at the4�-position to retain �-activity. For example,ritodrine (20) has only a 4�- OH for R4, yetretains good �-activity with the large substitu-ent on the nitrogen, making it �2 selective.

If R4 is only a 3�- OH, however, activity isreduced at �-sites and almost eliminated at�-sites, thus affording selective �-agonistssuch as phenylephrine (11) and metaraminol(8). Further indication that �-sites have awider range of substituent tolerance for ago-nist activity is shown by the 2�,5�-dimethoxysubstitution of methoxamine (9), which is aselective �-agonist that also has �-blocking ac-tivity at high concentrations.

When the phenyl ring has no substituents(i.e., R4 � H), phenylethylamines may haveboth direct and indirect activity. Direct activ-ity is the stimulation of a receptor by the drugitself, whereas indirect activity is the result ofdisplacement of norepinephrine from its stor-age granules, resulting in stimulation of thereceptor by the displaced norepinephrine. Be-cause norepinephrine stimulates both �- and�-sites, indirect activity itself cannot be selec-tive; however, stereochemistry of R1, R2,and/or R4 may also play a role.

For example, ephedrine erythro-(5) andpseudoephedrine threo-(5) have the same sub-stitution pattern and two asymmetric centers,so there are four possible stereoisomers. Thedrug ephedrine is a mixture of the erythro en-antiomers (1R,2S) and (1S,2R); the threo pair

of enantiomers (1R,2R) and (1S,2S) consti-tute pseudoephedrine (�-ephedrine). Analo-gous to the catechol �-methylnorepinephrine(65, the active metabolite of methyldopa), theephedrine stereoisomer with the (1R,2S) ab-solute configuration has direct activity on thereceptors, both � and �, as well as an indirectcomponent. The ephedrine (1S,2R) enantio-mer has primarily indirect activity. Pseudo-ephedrine, the threo diastereomer of ephed-rine, has virtually no direct activity in either ofits enantiomers and far fewer CNS side effectsthan those of ephedrine.

Other phenylethylamines, such as amphet-amine and methamphetamine, which lackboth ring substituents and a side chain hy-droxyl, are sufficiently lipophilic to readilycross the blood-brain barrier and cause dra-matic CNS stimulation, principally throughindirect activity. The clinical utility of am-phetamine and its derivatives is entirely basedon CNS stimulant and central appetite sup-pressant effects.

Thus, tamsulosin has no utility in treatinghypertension, but far fewer cardiovascularside effects than those of terazosin and dox-azosin in treating BPH.

5.1.5 Imidazolines and Guanidines. Althoughnearly all �-agonists are phenylethanolaminederivatives, �-adrenoceptors accommodate afar more diverse assortment of structures(80). Naphazoline (29), oxymetazoline (30),


tetrahydrozoline (31), and xylometazoline(32) are selective �1-agonists and thus are va-soconstrictors. They all contain a one-carbonbridge between C-2 of the imidazoline ring anda phenyl substituent; thus, the general skeletonof a phenylethylamine is contained within thestructures. Lipophilic substitution on the phe-nyl ring ortho to the methylene bridge appearsto be required for agonist activity at both typesof �-receptor. Bulky lipophilic groups attachedto the phenyl ring at the meta or para positionsprovide selectivity for the �1-receptor by dimin-ishing affinity for �2-receptors.

Closely related to the imidazoline �1-ago-nists are the aminoimidazolines, clonidine(35), apraclonidine (33), brimonidine (34); andthe structurally similar guanidines, guana-benz (36) and guanfacine (37). Clonidine wasoriginally synthesized as a vasoconstrictingnasal decongestant but in early clinical trialswas found to have dramatic hypotensive ef-fects, in contrast to all expectations for a vaso-constrictor (90). Subsequent pharmacologicinvestigations showed not only that clonidinedoes have some �1-agonist (vasoconstrictive)properties in the periphery but also thatclonidine is a powerful agonist at �2-receptorsin the CNS. Stimulation of central postsynap-tic �2-receptors leads to a reduction in sympa-thetic neuronal output and a hypotensiveeffect. A very recent review thoroughly dis-cusses the antihypertensive mechanism of ac-tion of imidazoline �2-agonists and their rela-tionship to a separate class of imidazolinereceptors (91).

Similar to the imidazoline �1-agonists,clonidine has lipophilic ortho substituents onthe phenyl ring. Chlorines afford better activ-ity than methyls at �2 sites. The most readilyapparent difference between clonidine and the�1-agonists is the replacement of the CH2 onC-1 of the imidazoline by an amine NH. Thismakes the imidazoline ring part of a guanidinogroup, and the uncharged form of clonidineexists as a pair of tautomers. Clonidine has apKa value of 8.05 and at physiologic pH isabout 82% ionized. The positive charge isshared over all three nitrogens, and the tworings are forced out of coplanarity by the bulkof the two ortho chlorines as shown.

The other imidazolines, (33) and (34), weresynthesized as analogs of (35) and were dis-covered to have properties similar to those of�2-agonists. After the discovery of clonidine,extensive research into the SAR of central �2-agonists showed that the imidazoline ring wasnot necessary for activity in this class. For ex-ample, two ring-opened analogs of (35) result-ing from this effort are guanabenz (10) andguanfacine (37). These are ring-opened ana-logs of clonidine, and their mechanism of ac-tion is the same as that of clonidine.

Tolazoline (41) has clear structural simi-larities to the imidazoline �-agonists, such asnaphazoline and xylometazoline, but does nothave the lipophilic substituents required foragonist activity. Phentolamine (40) is also animidazoline �-antagonist but the nature of itsbinding to �-adrenoceptors is not clearly un-derstood.

5.1.6 Quinazolines. Prazosin (43), the firstknown selective �1-blocker, was discovered inthe late 1960s (92) and is now one of a smallgroup of selective �1-antagonists, which in-cludes two other quinazoline antihyperten-sives, terazosin (44) (25, 93) and doxazosin(42). The latter, along with tamsulosin (24),was discovered to block �1-receptors in theprostate gland and alleviate the symptoms ofbenign prostatic hyperplasia (BPH).

The first three agents contain a 4-amino-6,7-dimethoxyquinazoline ring system at-tached to a piperazine nitrogen. The onlystructural differences are in the groups at-tached to the other nitrogen of the piperazine,and the differences in these groups afford dra-matic differences in some of the pharmacoki-netic properties of these agents. For example,when the furan ring of prazosin is reduced toform the tetrahydrofuran ring of terazosin,the compound becomes significantly more wa-

5 Structure-Activity Relationships 31

ter soluble (94), as would be expected, giventetrahydrofuran’s greater water solubilitythan that of furan.

5.1.7 Aryloxypropanolamines. In general,the aryloxypropanolamines are more potent�-blockers than the corresponding aryletha-nolamines, and most of the �-blockers currentlyused clinically are aryloxypropanolamines.Beta-blockers have found wide use in treatinghypertension and certain types of glaucoma.

At approximately this same time, a new se-ries of 4-substituted phenyloxypropanolo-lamines emerged, such as practolol, whichselectively inhibited sympathetic cardiac stim-ulation. These observations led to the recogni-tion that not all �-receptors were the same,which led to the introduction of �1 and �2 no-menclature to differentiate cardiac �-recep-tors from others.

Labetalol (26) and carvedilol (59) have un-usual activity, in that they are antihyperten-sives with �1-, �1-, and �2-blocking activity. Interms of SAR, you will recall from the earlierdiscussion of phenylethanolamine agoniststhat, although groups such as isopropyl andt-butyl eliminated �-receptor activity, stilllarger groups could bring back �1-affinity butnot intrinsic activity. Thus these two drugshave structural features permitting binding toboth the �1- and both �-receptors. The�-blocking activity of labetalol is approxi-mately 1.5 times that of its �-blocking activity.The more recently developed carvedilol has anestimated �-blocking activity 10 to 100 timesits �-blocking activity.

A physicochemical parameter that has clin-ical correlation is relative lipophilicity of dif-ferent agents. Propranolol is by far the mostlipophilic of the available �-blockers and en-


ters the CNS far better than less lipophilicagents, such as atenolol or nadolol. Lipophilic-ity as measured by octanol/water partitioningalso correlates with primary site of clearance.The more lipophilic drugs are primarilycleared by the liver, whereas the more hydro-philic agents are cleared by the kidney. Thiscould have an influence on choice of agents incases of renal failure or liver disease (27).

6 RECENT DEVELOPMENTS

Recently, major research efforts in develop-ment of adrenergic drugs have focused largely

on efforts to discover new selective �1A-antag-onists for treatment of prostatic hypertrophyand to develop selective �3-agonists for use intreating obesity and type 2 diabetes.

6.1 Selective �1A-Adrenoceptor Antagonists

The successful application of tamsulosin (24)to the treatment of BPH with minimal cardio-vascular effects has led to an extensive effortto develop additional antagonists selective forthe �1A-receptor. Phenoxyethylamine (102,KMD-3213), a tamsulosin analog, has been re-ported to be in clinical trial in Japan, as has(103) (95).

6 Recent Developments 33

Other series of highly selective �1A-antag-onists, and representative examples, arearylpiperazines, arylpiperidines, and piperi-dines, represented by (104), (105), and (106),respectively. Several compounds in these se-ries have entered clinical trials, but little hasbeen reported about the outcomes (95). In ad-dition to the review by Bock (95), two other

very thorough reviews of this field have re-cently been published (96, 97).

6.2 Selective �3-Agonists

The other major area of recent emphasis inadrenergic drug research has been develop-ment of selective �3-agonists to induce lipoly-sis in white adipose tissue. This area has beenextensively reviewed (4, 7, 8, 55, 98). Becauseobesity and diabetes are reaching epidemicproportions in the United States, an effectiveweight reduction has enormous therapeuticand market potential (99). As a consequence,there is a veritable avalanche of potential newdrugs being published. To date several com-pounds that looked promising in receptor as-says and animal studies have entered clinicaltrials and failed. The reader should consultthe listed reviews for extensive descriptions ofthe progress in this field through 2000. Someof the most promising recent candidates havebeen an extensive series of 3�-methylsulfon-amido-4�-hydroxyphenylethanolamines pre-pared by competing groups. Compounds (107)(BMS-194449) and (108) (BMS-196085) haveboth gone into clinical trial but are reported tohave failed (100, 101).


In a second series, compounds (109–111)were reported as the most active derivatives inthe compounds reported in each study (102–104). Finally, compounds (112) and (113)from the same publication were reported to beamong the most potent and selective human�3-agonists known to date (105).

Another group reported another series ofvery selective �3-agonists in a series of cya-noguanidine compounds. The most potent andselective in the series were reported to be(114) and (115) (106).

The rate of publication in the two areas ofselective �1A-antagonists and selective �3-ago-nists continues very high through the timethis chapter was written. There is a large mar-ket for a successful drug(s) in either of theseareas and the level of competition in these ar-eas will continue to be intense.

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Adrenergics and Adrenergic- Blocking Agents

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