Proposals for the Classification and Nomenclature of Functional Receptors for Hydroxytryptamine

8/3/2019 Proposals for the Classification and Nomenclature of Functional Receptors for Hydroxytryptamine

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NeurophmwologyVol. 25,No. 6, pp. 563416,1986 0028-3908/863.00 0.00Frintcdn Great Britain Pergamon Journals Lrd

COMMENTARYPROPOSALS FOR THE CLASSIFICATION AND

NOMENCLATURE OF FUNCTIONAL RECEPTORSFOR 5HYDROXYTRYPTAMINE

P. B. BRADLEY, G. ENGEL,* W. FENIUK,~J . R. FOZARD,~ P . P . A. HUMPHREY,~D. N. MIDDLEMISS,~*E. J. MYLECHARANE,~B. P. R ICHARDS ON* nd P . R. SAXENA~

Department of Pharmacology, The University of Birmingham, The Medical School, Birmingham Bl52TJ, England, rPreclinica1 Research Department, Sandoz Ltd, CH-4002 Basle, Switzerland, BiologyDivision, Glaxo Group Research Ltd, Ware, Herts SG12 ODJ, England, 4Merrell Dow Research Institute,Strasbourg Center, 16, rue dAnkara, 67084 Strasbourg Cedex, France, 5Department of Pharmacology,University of Sydney, Sydney, NSW 2006, Australia and 6Department of Pharmacology, ErasmusUniversiteit Rotterdam, Postbus 1738, 3000 DR Rotterdam, The Netherlands!&mmuy-As a result of controversy in the literature regarding the classification and nomenclature offunctional receptors for 5-hydroxytryptamine (5-HT), a framework for classification is proposed. Theformulation of these proposals has only been made possible by the recent advent of new drug tools.It is considered that there are three main types of S-HT receptor, two of which have been wellcharacter&d pharmacologically, using selective antagonists, and which it is proposed to name S-HT, andS-HT,. These two groups broadly encompass the D and M receptors, respectively, which Gaddumidentified in the guinea-pig ileum (Gaddum and Picarelli, 1957). The 5-HT, receptor, which mediates avariety of actions of 5-HT, has been definitively shown to correlate with the S-HT, binding site in thebrain. No binding studies in brain tissue have yet been published with radiolabelled ligands specific forS-HT, receptors.A number of other actions of 5-HT appear to be mediated via receptors distinct from 5-HT, or 5-HT,receptors. Since selective antagonists are not yet available, these receptors cannot be definitivelycharacterised, although in many cases they do have some similarities with 5-HT, binding sites, which area heterogeneous entity. Criteria are proposed for tentatively classifying these receptors as 5-HT,-like(Table 1). Definitive characterisation of these receptors will await the identification of specific antagonists.This classification of 5-HT receptors into three main groups (Table 1) is based largely, but notexclusively, on data from studies in isolated peripheral tissues where definitive classification is possible.However, it is believed that this working classification will be relevant to functional responses to 5-HTin the central nervous system.

Key words: 5-HT, 5-HT, receptors, 5-HT, receptors, 5-HT, receptors, 5-HT agonists, 5-HT antagonists.

It is abundantly clear that significant advances havebeen made in our knowledge of the pharmacology of5hydroxytryptamine (5-HT; serotonin) over the lastfive years or so (see below). However, there is someconfusion about the precise classification of types of5-HT receptors and hence their nomenclature (seeFozard, 1984a; Humphrey, 1984; Peroutka, 1984a,b). The situation is compounded in the literature bya number of speculative claims and extrapolationsfrom ligand binding data made without regard to anyfunctional correlate. The receptors which areclassified here are those which mediate, and hence areessential for, the actions of 5-HT in both the periph-ery and the brain, and unequivocal characterisationof these can only come from functional studies. Theseproposals attempt to accommodate the current stateof knowledge and to provide a unifying concept onwhich to build and elaborate. The data considered inthe present analysis come ,from both functional andligand binding studies so as to simplify our under-*Present address: Continent01 Pharma, Part Scientifique deLouvain-la-Neuve, Rue Grandbonpre 11, 1348 Mont-St-Guibert, Belgium.

standing wherever possible by correlation of bindingsites with pharmacological receptor types. Thedefinitive characterisation and classification of func-tional 5-HT receptors can only be effected by reliablefunctional studies carried out by workers who havetaken steps to avoid the pitfalls which await theunwary investigator. These pitfalls have been exten-sively described (e.g. Furchgott, 1972; Kenakin, 1982;Humphrey, 1984) but are often ignored.

Major advances in our knowledge have un-doubtedly arisen as a result of new drug tools recentlyidentified such as the antagonists ketanserin, MDL72222 (laH,3c(,5aH-tropan-3yl-3,5dichlorobenzoate)and ICS 205-930 [(3a-tropanyl)-lH-indole-3-carboxylic acid ester] and the agonists, 5-carboxami-dotryptamine and 2-methyl-5-hydroxytryptamine(see below). However, the situation has been compli-cated by rapid changes in the state of the art,coupled with the lack of a consensus on how toproceed with the classification and nomenclature oftypes of 5-HT receptors. The proposals presentedhere are intended to provide a framework to accom-modate current controversies and help to avoid themin the future.

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564 P. B. BRADLEY et al.HJSTORJCAL PERSPECTJVE

The first major iandmark in our understanding ofthe different types of S-HT receptors came from thework of Gaddum and Picarelli (1957) who presentedsound evidence for the existence of two pharma-cologically distinct types of receptor for 5-HT inguinea-pig ileum, one mediating contraction of thesmooth muscle (D) and the other mediating depo-larisation of the cholinergic nerves (M). However,the drug tools at their disposal, phenoxybenzamine(dibenzyfine) and morphine, were not specific 5-HTreceptor blocking drugs and are of little or no valueas tools for the overall classification of S-HT recep-tors (see Humphrey, 1984 for refs). Subsequently theterm D-receptor was applied to receptors in avariety of other smooth muscle preparations (includ-ing that of stomach fundus and uterus of the rat andaorta of the rabbit) where lysergic acid diethylamideand its derivatives (including methysergide)specifically antagonised the contractile actions of5-HT (see Gyermek, 1966). This extrapolation with-out comparison of antagonist dissociation constantshas, with the benefit of hindsight, been criticised(Humphrey, 1983). Recent studies moreover indicatethat the guinea-pig ileum also contains 5-HT receptortypes other than those described by Gaddum andPicarelli; one type appears to mediate relaxationof smooth muscle (Feniuk, Humphrey and Watts,1983) another inhibition of the release of acetyl-choline from cholinergic nerves (Kilbinger andPfeuffer-Friederich, 1985) and another depolarisationof non-cholinergic neurones (Buchheit, Engel,Mutschler and Richardson, 1985). Likewise, some ofthe effects of 5-HT in other preparations are mediatedby receptors which are neither of the D or Mtype (see Humphrey, 1983, 1984 for Refs). It is cleartherefore that any new classification should takeaccount of these new facts.The second major development, which occurredrelatively recently, was the identification of variousradioligand binding sites for 5-HT in brain tissue. In1979, Peroutka and Snyder presented evidence fortwo distinct 5-HT binding sites for which lysergic aciddiethylamide has a high affinity. At one site, termed5-HT,, 5-HT also has a high affinity, whilst at theother, termed 5-HT,, spiperone has a high affinity.Subsequent studies have clearly shown that theaffinities of a variety of S-HT antagonists for the5-HT, site correlate well with those at D receptors,measured in functional studies in vascular and gas-trointestinal smooth muscle (Humphrey, Feniuk andWatts, 1982; Engel, Hoyer, Kalkman and Wick,1984, 1985; Maayani, Wilkinson and Stollak, 1984).There is also a substantial amount of evidence tocorrelate 5-HT, binding sites with receptors mediat-ing a variety of responses to 5-HT in the brain andon platelets (see Leysen, 1984; Leysen, de Chaffoy deCourcelles, De Clerck, Niemegeers and Van Neuten,1984). Since the 5-HT, site is so well characterised the

te~inology has already come into common use evenfor receptors involved in functional studies.The situation regarding the 5-H-f, site is much lessclear despite the fact that 5-HT has a high affinity (in

the nanomolar range) for this site. Thus, there is stilldoubt and controversy about its functionalsignificance (e.g. Fozard, 1983a; Leysen, 1984). How-ever, there is evidence for the sub-division of 5-HT,binding sites. Thus, on the basis of atypical displace-ment curves and the use of spiperone, Pedigo, Yam-amura and Nelson (1981) demonstrated two distinctbinding sites for [H]5-HT in the brain of the rat; the.%HT,, site shows high affinity for spiperone, whereasthe 5-HT,, site has low affinity for spiperone. Thetetralin derivative, 8-hydroxy-2-(di-~-propylamino)-tetralin (8-OH-DPAT) has been subsequently shownto display both high affinity and selectivity for the5-HT,, site (Middlemiss and Fozard, 1983). A thirdsubtype of the 5-HT, recognition site, designated5-HT,c, has recently been proposed based on the highaffinity displacement of [HIS-HT by the ergot deriv-ative, mesulergine (Pazos, Hoyer and Palacios, 1985).Despite this evidence for the heterogeneity of the5-HT, recognition sites, it is considered that devel-opments have not progressed to the point where itwould be profitable to consider these in aclassification of 5-HT receptors.However, as already mentioned, there is goodevidence to show that, in some preparations, the5-HT receptors are not of the D or M type (e.g.pre-junctional inhibition of neurotransmitter release)and that they have similar characteristics to the5-HT, site (Feniuk, Humphrey and Watts, 1979;Engel, Gothert, Miiller-Schweinitzer, Schlicker,Sistonen and Stadler, 1983; Kilbinger and Pfeuffer-Friedrich, 1985; Charlton, Bond and Clarke, 1986).The 5-HT receptors which mediate the relaxation ofsmooth muscle and tachycardia can also be describedas 5-HT,-like (Trevethick, Feniuk and Humphrey,1984; Saxena, Mylecharane and Heiligers, 1985b;Connor, Feniuk, Humphrey and Perren, 1986),though on the basis of agonist data they do notappear identical to those inhibiting transmitter re-lease (see Humphrey, 1984). Definitive character-isation and correlation of such pharmacological re-ceptors will only come from future research and willrequire the identification of potent and selectiveantagonists, analogous to the potent, selective S-HT,receptor antagonists such as ketanserin, which havebeen invaluable for characterisation purposes. Untilthen this poorly defined and apparently hetero-geneous group of receptors can only be referred to as5-HT,-like.

A CLASSIFICATION AND NOMENCLATUREOF !!-HT RECEPTORS

With the recent discovery of a variety of drugsacting selectively at 5-HT receptors the time is nowappropriate to consider a new nomenclature to take


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Classification of 5-HT receptors 565account of Gaddums D and M receptors and tointegrate this classification with that of Peroutkasand Snyders binding site classification of 5-HT, andS-HT,. However, neither system of classification is byitself sufficiently comprehensive since the M recep-tor is not the same as the 5-HTi or 5-HT, binding siteand some S-HT receptors are clearly not D or Mreceptors (see Humphrey, 1984). Furthermore, somedrugs known as D receptor antagonists (e.g. lyser-gic acid diethylamide and methysergide) have highaffinities for both S-HT, and 5-HT, binding sites.Despite these apparent complexities, all the evidenceto date suggests that there are three main groups of5-HT receptor type and clearly neither system ofclassification can eclipse the other. For simplicity, aS-HT, system of nomenclature is suggested, whichattempts to correlate receptors mediating functionalresponses with equivalent radioligand binding sites(Table 1).

As discussed above, it is now apparent that theD receptors in the guinea-pig ileum and rabbitaorta are similar to or the same as the 5-H1; bindingsite and since the latter appellation is now morecommonly used, it is proposed that they should bereferred to as 5-HT, receptors. The M receptor hasno established binding site equivalent (but seeGershon, Takaki, Tamir and Branchek, 1985) andhence it is named the 5-HT, receptor. The nature ofthe 5-HT1 binding site and its functional correlatesare still under investigation but for the foreseeablefuture it is suggested that receptors which are clearlynot 5-HT, or 5-HT, and which have the character-istics defined below (see Table l), should be referredto as 5-HT,-like. Detailed justification for theseproposals which integrate a number of similar pro-posals recently made in the literature (see Humphrey,1983, 1984; Fozard, 1984a; Kalkman, Engel andHoyer, 1984; Verdouw, Jennewein, Heiligers, Dun-cker and Saxena, 1984) are outlined below. Since thefunctional responses associated with 5HIT,-likereceptors are only now being identified, these recep-

tors will be discussed in more detail than the morefully characterised 5-HT, and 5-HT, receptors.S-HT,-LIKE RECEPTORS

The principal characteristics of the 5-HT, recog-nition sites defined by Peroutka and Snyder were thehigh affinity of recognised 5-HT receptor agonistsand the relatively low affinity of classical S-HTreceptor antagonists (now generally considered as5-HT, receptor antagonists) such as methysergide,cyproheptadine and cinanserin. It is a considerablehandicap to the definition of this site that no selectiveantagonists have yet been described. Moreover, asdiscussed above, the 5-HT, radioligand binding site isclearly not a homogeneous entity. Notwithstandingthese obvious disadvantages it is thought to be appro-priate to adopt the term 5-HT,-like at this stage,However, two important points must bc made: firstly,the criteria suggested for the identi~cation of5-HT,-like receptors have deliberately been kept asbroad as possible to allow scope for modification asknowledge advances; secondly, although the5-HT,-like receptor has pharmacological similarityto the 5-HT, recognition site it may not necessarily beidentical to it. In other words, it is the criteria definedbelow which, at this stage, define a 5-HT,-likereceptor and not the necessity for identity with the5-HT, binding site.Criteria for characterisat ion ofS-HT,-li ke recepto rs

The first and most important criterion for thedefinition of any receptor, that the agonist responseshould be blocked by antagonists with high potencyand selectivity for that site, cannot be satisfied in thecase of the 5-HT,-like receptor, since no suchantagonist for this site has yet been described. Severalcompounds do, however, have appreciable affinitiesfor the 5-HT, binding site, including methiothepinand methysergide (which have even higher affinities at5-HT, receptors), and a number of stereoselective

Table 1.Sunnnary of proposals for classification and nomenchuure of functional 5-HT xeptorsProposedreceptornomenclature

5-HT,-likeTypical responses

Prejunctional inhibitionof neuronal transmitterrelease, smooth musclerelaxation, contractionof some vascular smoothmuscles and tachycardiain the cat

SeIectiveagonists5Carboxamidotryptamine

SelectiveantagonistsMcthysergide*Methiothepint

Equivalentbinding site5-HT,?

S-HT,

5-HT,

Gastrointestinal andvascular smooth musclecontraction, plateletaggregation, neuronaldepolarisation.~la~~t~on ofneriuheral neurones.

-

2-Methyl-S-hydroxy~p~ine

KetanserinCyproheptadineMethysergide

CocaineMDL 72222

S-HT,

None. . ICS 205-930*Weak antagonist (or partial agonist) at some $HT,-like receptors.tLess potent antagonist than at 5-HT, receptors but inactive at 5-HT, receptors.


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566 P. B. BRADLEY et al.

Table 2. Functional responses which appear

Responses to 5-HTIn vitroNeuronal inhibition

Neuronal inhibition

Species/location

Rat brain

Dog saphenous vein

Antagonism by methiothepinor methysergide*

Schlicker and Giithert (1981);Cox and Ennis (1982);Engel et al. (1983, 1986)Feniuk et al. (1979)

Neuronal inhibitionNeuronal inhibitionVascular smooth muscle contractionVascular smooth muscle relaxationSmooth mucle contractionSmooth muscle relaxationIn via0TachycardiaHypotension

Vasodilation, hypotensionConstriction of carotid artetiovenous

anastomoses and dilatation of arterioles

Rat kidneyGuinea pig ileumDog saphenous veinCat saphenous veinRat stomach fundusGuinea pig ileum

CatRat

CatPig

Charlton et al. (1986)North et al. (1980);Kilbinger and Pfeuffer-Friederich (1985)Apperley et al. (1980);Apperley and Humphrey (1986)Feniuk et al. (1983)Frankhuyxen and Bonta (1974);Cohen and Wittenauer (1985)Feniuk et al. (1983)

Saxena et al. (1985b);Connor et al. (1986)Fozard and Leach (1968);Dalton, Feniuk and Humphrey (1985);Saxena and Lawang (1985)Connor et al. (1986)Saxena et al. (unpublished)

*No potent sr,l&ive5-HT,-like receptor blocking drugs have yet been described. Note that methysergide sometimes displays partial

/I-adrenoceptor antagonists such as propranolol,pindolol and cyanopindolol (Middlemiss, Blakebo-rough and Leather, 1977; Leysen, Awouters, Kennis,Laduron, Vandenberk and Janssen, 1981; Nahorskiand Willcocks, 1983; Middlemiss, 1985a; Engel,Gdthert, Hoyer, Schlicker and Hillenbrand, 1986). Inline with the intention to keep the definition of the5-HT,-like receptor as broad as possible at thisstage, it is proposed as the first criterion foridentification of 5-HT,-like receptors that theresponse mediated should be antagonised by methi-othepin and/or methysergide. Stereoselective block-ade by certain P-adrenoceptor antagonists cannot bea criterion since many 5-HT,-like receptors mediat-ing functional responses are not blocked by theseagents.The second criterion for a pharmacological re-sponse to be mediated through 5-HT,-like recep-tors is that antagonists with high selectivity for otherrecognised 5-HT receptor sites should be inactive.Thus, compounds like ketanserin, which has affinityfor the 5-HT, recognition site and negligible affinityfor the 5-HT, site (Leysen et al., 1981), should not beantagonists at the putative 5-HT,-like receptor.Other classical 5-HT receptor blocking agentswhich are similarly able to discriminate between5-HT, and 5-HT, recognition sites include cy-proheptadine and cinanserin (Leysen et al., 1981). Bysimilar reasoning, compounds with high selectivityfor the 5-HT, receptor yet with essentially no affinityfor the 5-HT, recognition site, such as MDL 72222(Fozard, 1984b), ICS 205-930 (Richardson, Engel,Donatsch and Stadler, 1985), metoclopramide(Fozard and Mobarok Ali, 1978) (-)cocaine(Fozard, Mobarok Ali and Newgrosh, 1979) and

nor( -)cocaine (Fozard, 1983b), should not antago-nise responses mediated through the putative5-HT,-like receptor.

The third criterion is based on agonists. Severalcompounds display a high affinity for the 5-HT,recognition site. These include 5-methoxy-3( 1,2,3,6-tetrahydropyridin-4-yl) 1H indole succinate (RU24969; Hunt and Oberlander, 1981; Middlemiss,1985b) and 5-carboxamidotryptamine (Feniuk,Humphrey and Watts, 1981) which displaces13H]5-HT binding with a potency (-log K, = 8.64)somewhat greater than that of 5-HT (-log K, =8.51; Engel et al., 1983). In contrast, 5-carboxamido-tryptamine is 26 times less active than 5-HT inactivating the 5-HT, receptor of the rabbit aorta(Feniuk et al., 1981) and more than 50 times lessactive as a stimulant of 5-HT, receptors of theguinea-pig ileum (Humphrey, 1984). Thus, theactions of 5-HT at 5-HT,-like receptors should bemimicked by 5carboxamidotryptamine (with a po-tency at least equal to that of 5-HT; e.g. see Feniuk,Humphrey, Perren and Watts, 1985a). However, RU24969 does not exhibit such selectivity (Feniuk, un-published observations), being of similar potencyrelative to 5-HT in both the rabbit aorta (containing5-HT, receptors) and dog saphenous vein (containing5-HT,-like receptors). This highlights the danger ofputting too much emphasis on agonist data. It isevident that 5-HT itself has a low affinity for the5-HT, binding site but a high affinity for the 5-HT,binding site and that most 5-HT receptor agonistsappear to be 5-HT, selective as judged from bindingstudies alone (e.g. see data in Martin and Sanders-Bush, 1982).Thus, the following criteria are proposed for a


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Classification of 5-HT receptors 567to be mediated by S-HT,-like receptors

Resistance o antagonismby 5-HT, receptorblocking drugs Resistance to antagonism by S-HT,receptor btockina drum Action of 5-HT mimickedbv 5-carboxamidotrwtaminetEngel ef al. (1983)

Van Nueten et al. (1981);Watts et al. (1981)Char&on ef 01. (1986)North ef al. (1980);Kilbinger and PfeufTer-Friederich (1985)Apperley et al. (1980);Feniuk et al. (1985a)Fen&k et a l. (1983)Van Nueten, Leysen, Schuurkes andVanhoutte (1983); Cohen and Wittenauer (1985)Feniuk et al. (1983)

Engel et al. (1983);Middlemiss (unpublished) Engel e( al. (1983, 1986)

McGrath (1977); Feniuk er al. (1981);Feniuk et al. (1979) Engel et al. (1983)Charhon ef al. (1986) Charlton et al. (1986)Kilbinger and Pfeuffer-Friderich (1985) No dataCurro, Greenberg, Verbeuren andVanhoutte (1978)No dataFczard (1984b)

Feniuk et of. (1985a)Feniuk et al. (1984)Feniuk (unpubjis~d)

No data Feniuk er ui. (1984)Saxena et al. (1985b);Connor ef al. (1986)Kalkman, Boddeke, Doods,Timmennans and Van Zwieten (1983);Saxena and Lawang (1985)Connor et al. (1986)Saxena and Verdouw (1982);Verdouw et al. (1984)

Saxena er al. (1985b)Forard (1984b);Dalton et a/. (1985)Saxena er al. (1985b)Saxena er al. (unpublished)

Connor ef al. (1986);Saxena er al. (1985b)Saxena and Lawang (1985)

Connor et al. (1986)Saxena and Verdouw (1985)agonistic ctivity.@electivity only relative (see Humphrey, 1984).

response to be defined as being mediated through5-HT,-like receptors:

1. Susceptible to antagonism by methiothepinand/or methysergide (which sometimes displays par-tial agonistic activity) usually at doses or concen-trations greater than those needed to block S-HT,receptors.

2. Resistant to antagonism by selective S-HT,receptor antagonists such as ketanserin and cypro-heptadine and by S-HT, receptor antagonists such ascocaine, MDL 72222 or ICS 205-930.

3. Mi~cked by the selective 5-HT, agonist5~r~xa~do~pta~ne at ~ncentratio~ equal toor less than those of 5-HT.Dist ribution and function of putat ive S-HT,-lik ereceptors

A number of responses has been claimed in theliterature to be mediated through 5-HT, receptors;the details of those for which at least two out of theabove three criteria have been satisfied are presentedin Table 2. The most studied of these are discussedbelow.

The 5-HT auto receptor of the ventral neruous sys-tem of the rat. Agonist activity at the S-HT auto-receptor causes inhibition of transmitter releaseevoked by depolarising stimuli. As is clear from Table2, the properties of the autoreceptor present on theterminals of S-HT-containing neurones satisfy inlarge part the three criteria laid down above forclassification of a receptor as 5-HT,-like.

The inhibitory receptor for 5-NT on postganglionicsympathetic neurones. Two tissues have been particu-larly well studied in this context, the saphenous vein

of the dog (McGrath, 1977; Feniuk et al., 1979;Watts, Feniuk and Humphrey, 1981) and the per-fused kidney,. of the rat (Charlton et al., 1986).Activation of the pre-junctional S-HT receptor resultsin inhibition of depolarisation-induced release ofnoradrenaline from the sympathetic nerves of thesetissues. From Table 2, it is clear that the principalcriteria for mediation of the response by 5-HT,-likereceptors have been satisfied. Furthermore, it shouldbe noted that in the saphenous vein of the dog,methysergide has marked partial agonist activity atthe pm-junctional S-HT receptor (Watts et al., 1981)and an estimate of its affinity based on the concen-tration required to produce 50% of maximal in-hibition of release of noradrenaline is very similar toits known affinity at 5-HT1 binding sites (Peroutka,Lebovitz and Snyder, 1981). It is important to notethat even large concentrations of propranolol, pin-dolol or cyanopindolol were ineffective in antago-nising this pm-junctional effect of 5-HT (Watts et al.,1981; Charlton et al., 1986) and that the potency ofsome putative agonists of 5-HT,-like receptors didnot correlate with the affinities for 5-HT, bindingsites (Charlton et ul., 1986). This provides a goodexample where the criteria for a 5-HT,-like recep-tor have been largely satisfied yet a clear differencefrom the 5-HT, recognition site can be demonstrated.

The inhibitory receptor for 5-HT on ent eric choli-nergic neurones. Both electrophysiological and bio-chemical evidence indicates the presence of a 5-HTreceptor within the guinea-pig myenteric plexus, acti-vation of which results in inhibition of the release ofacetylcholine from the enteric cholinergic neurones(North, Henderson, Katayama and Johnson, 1980;


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568 P. B. BRADLEY etal.Kilbinger and Pfeuffer-Friederich, 1985). Despite thefact that no selective 5-HT,-like receptor agonisthas yet been described as mimicking the effect of5-HT at this site, other evidence strongly implicatesa 5-HT,-like receptor as the mediator of the re-sponse (Table 2).The recepto r for S-HT mediat ing contraction ofcertain blood vessels. Certain blood vessels, notablythe saphenous vein of the dog and basilar artery fromrabbit and man, respond to small concentrations of5-HT with contractile responses which are resistant toblockade by selective 5-HT, receptor blocking agents(Apperley, Feniuk, Humphrey and Levy, 1980; For-ster and Whalley, 1982; Peroutka, 1984a; Feniuk etal., 1985a; Bradley, Humphrey and Williams, 1986).The majority of the criteria for mediation of theseresponses through 5-HT,-like receptors aresatisfied (Table 2). The evidence is thus consistentwith a close similarity between the pre-junctionalreceptor in the saphenous vein of the dog (see above)and these post-junctional receptors, a conclusionreinforced by the highly significant correlation be-tween the potency of a number of agonists at bothsites (Feniuk et al., 1981; Miiller-Schweinitzer, 1981).The similarity extends, too, to the fact that meth-ysergide is a partial agonist of similar potency bothpre- and post-junctionally (Apperley et al., 1980;Watts et al., 1981; Peroutka, 1984a). There is alsoevidence that such receptors mediate vasoconstrictionin the arteriovenous anastomoses located in thecarotid circulation in vivo (Saxena, 1974; Saxena andVerdouw, 1982, 1985; Verdouw, Jennewein, Mierauand Saxena, 1985).

The recepto r for S-HT mediat ing relaxation ofsmooth muscle. S-Hydroxytryptamine induces relax-ation of some vascular and gastrointestinal smoothmuscle by a direct effect on smooth muscle (e.g.Feniuk et al., 1983; Trevethick et al., 1984). Thiseffect is selectively mimicked by %carboxamido-tryptamine (Feniuk, Humphrey and Watts, 1984;Trevethick, Feniuk and Humphrey, 1986) which is apotent vasodilator and hypotensive agent in anaes-thetised and conscious animals (Feniuk, Humphreyand Hunt, 1985b; Saxena and Lawang, 1985; Connoret al., 1986). In addition, 5-HT-induced relaxation ofvascular smooth muscle appears to be resistant toblockade by the 5-HT, receptor blocking drugketanserin and also propranolol (Van Nueten,Janssen, Van Beek, Xhonneux, Verbeuren and Van-houtte, 1981; Cocks and Angus, 1983; Feniuk et al.,1983) and yet can be blocked, albeit weakly, bymethysergide (Feniuk et aI., 1983; Cohen, Shepherdand Vanhoutte, 1983b). The evidence strongly impli-cates a 5-HT,-like receptor in the mediation ofthese responses (Table 2).

The recepto r for 5-HT mediat ing contraction of th estom ach fundus of the rat. 5-Hydroxytryptaminecauses powerful contractile responses on the ratfundic strip (Vane, 1957). To the extent that re-sponses are not antagonised by ketanserin or 5-HT,

receptor antagonists and that methiothepin is aneffective, though rather weak antagonist (Table 2)the receptor of the rat fundus can be said to be5-HT,-like. This interpretation is supported by thedemonstration of a significant correlation betweenthe potency of 19 antagonists of 5-HT on the fundusand their affinities for the 5-HT, recognition site(Leysen and Tollenaere, 1982). However, certainother pieces of evidence, apparently not supportive ofthis conclusion (Table 2) deserve comment. Thus,5-carboxyamidotryptamine, although mimicking theeffects of 5-HT on this tissue, is some 10 times lessactive than 5-HT in this respect (Feniuk, unpublisheddata) and hence significantly less active than wouldbe predicted from its relative affinity for the 5-HT,recognition site. Moreover, methysergide is at least asactive as an antagonist of 5-HT on the fundus(although it does not behave competitively) as it isagainst responses mediated through the 5-HT, recep-tor (Frankhuyzen and Bonta, 1974; Cohen andWittenauer, 1985).In conclusion, whilst the receptor mediating thecontractile responses to 5-HT in rat fundic strip(which has been referred to as a D receptor in thepast) clearly cannot be classified as either a 5-HT, or5-HT, receptor, it may be classified as 5-HT,-likeonly subject to the anomalies outlined above.

The receptor mediating tachycardia in the cat heart.Intravenous injection of 5-HT to anaesthetised orspinal cats induces tachycardia which is not mediatedthrough /3-adrenoceptors (Saxena et al., 1985b). The5-HT receptor involved may be the same as the 5-HTreceptor which mediates relaxation of smooth muscle(Connor et al., 1986). Reference to Table 2 shows allthe criteria to have been satisfied allowing the conclu-sion that 5-HT,-like receptors mediate the re-sponse. As in the stomach fundus of the rat, thisresponse has previously been regarded as a Dreceptor effect (see Saxena et al., 1985b).Further class$cat ion of dHT,-l ik e receptors

It bears emphasis that the category 5-HT,-like asdefined here is intended as an interim classification toserve until new developments force its modification.Such developments could come as a result of thediscovery of compounds with improved selectivity forthe 5-HT, binding site and its subtypes and the useof such agents in functional tests. Increasing numbersof such drugs are now being described includingbuspirone (Glaser and Traber, 1983), 8-OH-DPAT(Middlemiss and Fozard, 1983), TVX Q 7821[2 - (4 - (4 - (2 - pyrimidinyl) - 1 piperazinyl) - butyl - I,2 -benzisoltriazol- 3(2H)one - 1,l - dioxidehydrochloride](Dompert, Glaser and Traber, 1985), BEA 1654[N-(3-acetylaminophenyl)piperazine] (Verdouw etal., 1985). Appropriate functional analyses with suchagents should facilitate attempts to arrive at a com-prehensive classification of 5-HT,-like receptors. Inthis context, evidence for the inhibitory receptor for5-HT on enteric cholinergic neurones of the guinea-


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Classification of 5-I-IT receptors 56 9pig being of the 5-HTrA subtype has appeared(Fozard and Kilbinger, 1985), while it has beensuggested that the S-HT autoreceptor in the brain isof the S-HT,, subtype (Engel et al., 1986). However,definitive characterisation of all such responses willawait the identification of potent, selective,competitively-acting blocking agents.

5.HT, R E C E PT O R STh e introduction of the term 5-I-IT, receptor by

Peroutka and Snyder (1979) to describe a 5-HTrecognition site in the brain with a low affinity for5-HT but with a high affinity for spiperone and otherclassical (so called D) 5-HT receptor blockingdrugs, such as methysergide and ~~rohep~dine, hasled many to investigate the correlates of this bindingsite with functional responses. The fact that someof these antagonists also have appreciable affinityfor the 5-HT, binding site (e.g. methysergide andmethiothepin) or are potent calcium antagonists(e.g. cyprohep~dine) has led to some confusion inattempts to correlate the 5-HT, binding site with thefunctional effects of 5-HT (see Leysen et al., 1981;Lowe, Mathews and Richardson, 1981). However,the identification of the 5-HT antagonist, ketanserin,which has a marked affinity for 5-HT, recognitionsites and a negligible affinity for 5-HT, recognitionsites {Leysen et al., 1981) provides a particularlyuseful tool with which to characterise these receptorspharmacologically.

Although certain agonists, such as S-carboxamido-tryptamine, appear to possess a degree of selectivityfor 5-HT,-like receptors, as far as is known, nocompound has yet been identified which showsmarkedly selective agonistic activity in preparationscontaining 5-HT, receptors.Criteria for the characterisat ion of .5-HT, receptors

1. Antagonists with a high affinity for 5-HT,recognition sites should show a similarly high antag-onistic potency at the putative 5-HT, receptor. Thus,compounds such as ketanserin, spiperone, meth-ysergide, pizotifen and cyproheptadine are all potentantagonists at S-HT, receptors with pA, values (be-tween 8.5 and 9.4) which are similar to their pKnvalues determined from ligand binding studies (seeHumphrey et al., 1982). Experiments with ketanserinare particularly important since this compoundshows negligible affinity for 5-HT, binding sites andis not a potent calcium antagonist (Van Nueten andVanhoutte, 1981). It should however be noted thatketanserin does show appreciable affinity fora-adrenoceptors and it is imperative to dissociatethose effects of S-HT which are mediated via stimu-lation of specific 5-HT receptors from those effectswhich may be mediated via a-adrenoceptors (seeFeniuk, 1984). In contrast, methysergide has negli-gible affinity for a-adrenoceptors. It should thereforebe necessary to determine the antagonistic potencies

of at least these two 5-HT receptor blocking drugsbefore the receptor subserving a given response canbe character&d as being of the 5-HT, type.2. The second criterion is that compounds with ahigh selectivity for other 5-HT receptor types shouldnot antagonise responses mediated through the puta-tive 5-HT, receptor. Thus, antagonists with a highselectivity for the 5-HT, receptor, e.g. cocaine, MDL72222 and ICS 205-930 are inactive at 5-HT, recep-tors. Unfort~ately, since no potent, selective, j-HT,-like receptor blocking drugs have yet beende&bed this particular criterion cannot be testedfully at this time.

3. No suitably selective agonist has been identified.Dist ribution and function of S-NT, recept ors

Table 3 summarises functional responses to S-HTboth in vivo and in vitro which appear to be mediatedby stimulation of 5-HT, receptors. This diverse list ofactions includes not only contraction of a variety oftypes of smooth muscle but also platelet aggregationand neuronal depolarisation (Fozard, 1984a). Inmany cases the classification as a 5-HT, receptor-mediated mechanism is tentative because strict mea-sures of the dissociation constants of 5-HT receptorblocking drugs and hence a comparison of equivalentvalues in ligand binding studies have only beencarried out in some smooth muscle preparations.Another complication is that while many potent5-HT, receptor blocking drugs (e.g. ketanserin) ap-pear to be competitive antagonists of 5-HT-inducedcontraction in vascular smooth muscle, they appearto be potent but unsurmountable antagonists in otherpreparations, e.g. the rat uterus (Ichida, Hayashi andTerao, 1983). Precisely why this is so is not yet clear.Interestingly, trazodone is a potent competitive an-tagonist of S-HT in the uterus (Wrigglesworth, 1983)and jugular vein of the rat (Cohen, Mason, Wiley andFuller, 1983a) but it is approx. 20-30 times weaker asa competitive antagonist in the rabbit aorta (Black,Brazenor, Gerskowitch and Leff, 1983). One possibleexplanation therefore is that S-HT, receptors areheterogeneous but it would be unwise to reach thisconclusion without considering the potential in-volvement of complicating experimental factors ormixed receptor populations (e.g. see Humphrey,1984).

It is evident that ketanserin and methyser~de areparticularly useful in characterising 5-HT, receptors.Ketanserin has the advantage of not only beinginactive at !I-HT, receptors but also having littleaffinity for the 5-HT,-like receptor.

5_HT, RECEPTORS

For many years the identification of 5-HT, recep-tors was hampered by the lack of specific antagonistsas drug tools. However, in 1979 it was shown thatM receptors, similar to those in the guinea-pigileum, mediated the release of noradrenaline from


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570

Responses to 5-HT

P. B. BRADLEY et al.Table 3. Functional responses which

Specific antagonismSpecies/location by ketanserin or methysergideIn vitroContraction ofvascular smoothmuscleContraction ofextra-vascularsmooth musclePlatelet aggregationIn vivaVasopressor responses

5_Hydroxytryptophan-induced head twitch5_Hydroxytryptophan-induced wet dog shakeOedemaUrinary bladder contraction(second phase)

Rabbit aorta

Rat tail arteryDog gastrosplenic vGuinea-pig tracheaRat uterusGuinea-pig ileum(atropine treated)CatRabbit and manPithed/anaesthetised rat

Conscious ratAnaesthetised catAnaesthetised guinea-pigConscious rat/mouseConscious ratRat pawAnaesthetised cat

Apperley, Humphrey and Levy, (1976);Feniuk et al. (1985a)Bradley, Humphrey and Williams (1985); Van Nueten etal. 1981)Van Nueten et al. (1981)Van Nueten, Leysen, Vanhoutte and Janssen (1982)Ichida et al. (1983)Engel et al. (1985)De Clerck, Xhonneux, Leysen and Jannsen (1984)No dataVan Nueten er nf. (1981);Feniuk, Humphrey and Perren (1982);Fozard (1982)Saxena and Lawang (1985);Dalton et al. (1985)Reiche and Frey (1983);Connor et al. (1986)Saxena and Lawang (1985)Malick, Dose and Barnett (1977)Colpaert and Janssen (1983);Yap and Taylor (1983)Ortmann, BischotT, Radeke Buech andDelini-Stula (1982)Saxena, Heiligers, Mylecharaneand Tio (1985a)

sympathetic nerves innervating the rabbit heart andcocaine was shown to be a specific, albeit weak,antagonist at these receptors (Fozard et al., 1979).Such studies led to the development of a potent andselective 5-HT, (M) receptor blocking drug, MDL72222 (Fozard, 198413). Work in parallel led to theidentification of even more potent 5-HT, antagonistsincluding ICS 205-930 (Richardson et al., 1985). Withthe availability of these specific antagonists, 5-HT,receptors have been identified in a variety of locationson peripheral efferent and afferent neurones (Fozard,1984a).A useful selective agonist is also available for thestudy of 5-HT, receptors. Thus, of a series of tryp-tamine analogues tested as agonists in a number oftest systems, 2-methyl-5-HT proved to have selectivestimulant effects at peripheral neuronal 5-HT, recep-tors (Richardson et al., 1985; see also Humphrey,1984).Criteria for the characterisat ion of 5-HT, receptors

For a response to be defined as being mediatedthrough 5-HT, receptors it should be:1. Susceptible to antagonism by (-)cocaine, MDL72222 or ICS 205-930 which are selective antagonistswith pA, values in the order of 6.0-7.0, 7.5-9.5 and8.0-l 1 O respectively.2. Resistant to antagonism by antagonists that areactive at 5-HT, receptors (e.g. ketanserin or meth-ysergide) or 5-HT,-like receptors (e.g. methi-othepin).

3. Mimicked by the selective 5-HT, agonist2-methyl-5-HT, which has a potency similar to thatof 5-HT itself.Dist ribution and function of 5-HT, recepto rs

The distribution and functions of receptors whichfulfil some, or all, of the criteria listed above for5-HT, receptors are summarised in Table 4. It isapparent from this table that these receptors for5-HT are invariably located on peripheral neuroneswhere they are responsible for eliciting the depolar-ising action of 5-HT. Nevertheless, this does notpreclude the possibility that receptors fulfilling thecriteria for designation as 5-HT, receptors may even-tually be found in the central nervous system or innon-neuronal locations.Heterogeneit y of 5-HT, receptors

Evidence for the existence of 5-HT, receptor sub-types stems from the recent observation thatsignificantly different pA, values for the same com-petitive antagonists have been obtained in differentbioassay systems. Thus, MDL 72222 yields a pA,value of 8.9 for 5-HT, receptors on post-ganglionicsympathetic nerve fibres in the rabbit heart, and apA, value of 7.9 on primary afferent neurones in thevagus nerve of the rabbit, but is a weak non-specificantagonist at 5-HT, receptors on enteric neurones inthe guinea-pig ileum (Donatsch, Engel, Richardsonand Stadler, 1984). Similarly, ICS 205-930 has pA,values on these systems of 10.6, 10.2 and 7.9 re-spectively (Richardson et nl., 1985). Moreover, ana-


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Classification of 5-HT receptors 571appear to be mediated by 5-HT, receptorsResistance to antagonism by 5-HT,recentor blocking drugs CommentsMDL 72222 inactive at10pM (Feniuk, unpublished observations)

No dataNo dataNo dataFozard (1984b); Richardson et al. (1985)Engel et al. (1985)No dataTaparelli (unpublished observations)Kalk;nan et al. (1984)

Dalton el al. (1985)No dataDhasmana e( al. (unpublished)Shearman (unpublished observations)No dataNot testedSaxena et al. (1985a)

Comparison of dissociation constants at the 5-HT, binding site with equivalentvalues from pharmacological studies suggests that the binding site and pharma-cological receptors are similar (see Humphrey, 1984).

Receptor in guinea-pig ileum is Gaddum and Picarellis original D-receptor(see Engel er al., 1984, 1985).5-HTs-binding sites have been identified on cat platelets.Inhibition of 5-HT-induced [sP]phosphatidic acid formation in human plateletsalso appears to be 5-HT, mediated (see Leysen et al., 1984).

Selective 5-HT, antagonist, pirenperone, potent antagonist of5-hydroxytryptophan-induced head twitch in mice (Green, OShaughnessy,Hammond, Schachter and Grahame-Smith, 1983). Effects of ketanserin notstudied.Although ketanserin not studied many classical 5-HT antagonists are potentinhibitors of 5-HT-induced rat paw oedema (Ortmann e( al., 1982).Second prolonged phase of contraction (first transient phase is 5-HT, mediated).

logues of ICS 205-930 have now been describedwhich discriminate between 5-HT, receptors in therabbit heart and those in the vagus nerve (Richardsonet al . , 1985). On the other hand, (-)cocaine is anon-selective antagonist which has a pA, value of6.0-6.5 on all three systems (Fozard et al., 1979;Engel and Richardson, unpublished observations).The foregoing suggests that subtypes of the 5-HT,receptor exist, but more rigorous studies with theselective antagonists are needed for their propercharacterisation.

CONCLUSIONSThis paper has reviewed the recent progress madein our understanding of the pharmacology of 5-HT

with a view to defining the broad criteria necessaryfor the characterisation and classification of 5-HTreceptors. Using these criteria, three distinct groupsof 5-HT receptors can be identified which have beennamed 5-HT,-like, 5-HT, and 5-HT,.

As emphasised at the outset, the proposedclassification of 5-HT receptors is intended to providea general framework which can be built upon asnew knowledge accumulates. It is recognised that,with the discovery of selective antagonists (particu-larly for the 5-HT,-like receptors), the proposedclassification will undergo modification and/or exten-sion. However, a plea must be made for investigatorsto exercise extreme caution before attempting todefine yet another 5-HT, receptor. Erroneous inter-pretation can readily result from, for example, mixedreceptor types mediating a common function.

Definitive characterisation (and hence naming) mustawait well controlled quantitative studies withpotent, selective, competitively acting receptor block-ing drugs.

This classification is based largely, but not exclu-sively, on data from studies in isolated peripheraltissues where definitive characterisation is possible.Nevertheless, specific drug tools are now available tocharacterise. 5-HTr and 5-HT, receptor mechanismswherever they exist, including the brain. There isevidence for the involvement of 5-HT, receptors inthe depolarising action of 5-HT in neurones of thecentral nervous system (McCall and Aghajanian,1980) as well as in 5-HT-stimulated inositol phos-pholipid hydrolysis (Conn and Sanders-Bush, 1985;Kendall and Nahorski, 1985). Moreover, 5-HT,-like receptors may mediate the hyperpolarisingaction of 5-HT on neurones in the brain, as well asits pre-junctional inhibitory action on neuronal trans-mitter release (Haigler and Aghajanian, 1977; Ennis,Kemp and Cox, 1981; Davies, Roberts and Wilkin-son, 1985). However, without good selective antago-nists, characterisation of 5-HT,-like receptormechanisms in both brain and periphery will be slow.As yet, 5-HT, receptors have not been identified inthe brain. Nevertheless, it is believed that the pro-posed classification of 5-HT-receptors will ultimatelybe shown to be relevant to studies in the centralnervous system.Authors Footnote-This publication has come about fol-lowing a Symposium on SHT, Peripheral and Central


10/14

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11/14

ClassifiMrionof 5-H-F receptors s73Receptors, and Function, which was held at BirminghamUniversity on April 1I, 1984, as mu+tof the Spring Meetingof the British P~~~a~l~~~~ Society. The Proceedings ofthe S~~sium were Fub~~sh~ as a Special fssue of thisJournal (Vol. 23, No. 12B, 1984). Following discussionsamong the participants, together with a number of thoseattending the Symposium, it was decided to set up aWorking Party to see if something oould be done about theunsatisfactory state concerning the classification of 5-HTreceptors. The present authors comprised the core of theWorking Party, although others participated from time totime and we should like to thank them for their con-tributions. A number of meetings was held and this Yom-mentary is the end result of the Working Partys dehber-ations.

-of ~~~ydroxyt~~t~ine- and methysergide with methi-otheDin at S-HT,-like receptors in dog saphenous vein.Br. j. Pkmmac. ri7: 131P. - _ _Apperley E., Humphrey P. P. A, and Levy 0. P. ff976)Receptors for S-hydroxytryptamine and noradrenaline inrabbit isolated ear artery and aorta. Br. J. Pharmae. !Rk21 l-221.Apper$ey E., Fe&& W., Hippy P. P. A. and Levy0. P. (L980) Evidence for two types &excitatory receptorfor 5-hydroxytryptamine in dog isoiated vasculature. &.J. Pharmac. 68: 215-224.Axami J., Foxard J. R., Round A. A. and Wallis D. I. (1985)The depoiarising action of ~-b~drox~t~ne onrabbit va# primary tierent and ~~~e~ neuranesand its selective blockade by MDL ?2222. Nuun~n-Scbmiedebergs Arch. Pharmac. 32% 423429.Black J. W., Braxenor R. M., Gerskowitch V. P. and LeffP. (I 983) The problem of ~su~o~~~bie antagonism in~hydroxy~t~i~ receptor classification. Br. .T_ !arr-muc. 8th 607P.Bradley P. B., Humphrey P. P. A. and Williams R. H. (1985)T~tamine-induced vasoconstrictor responses in ratcaudaf arteries are radiated nominally via~hydrox~~~~mine receptors. BP. j. ~~~~e. 84:939-925.Bradley P. B., Humphrey P. P. A. and Williams R. H. (1986)Evidence for the existence of 5-bydroxytryptamine recep-tors, which are not of the S-NT, type, mediating con-traction of is&a&d rabbit basilar artery- Br. .&Pbarmac.87:34.Buchbeit K. H., Engel G., Mutsch~er E. and RichardsonB. P. (198% Study of the contractile effect of5-hydr~x~t~F~~~e 1%HT) in the isolated longitudinalmuscle strip from guinea-pig ileum. Evidence for twodistinct release mechanisms. Satyr-Scbmjedebergs Arch,Fharmac. 329: 36-41.Charlton K. G., Bond R. A. and Clarke R. B. (1986) An~~~to~ p~j~n~~na~ 5-HT,-like receptor in the iso-fated per&r& rat kidney: apparent ~sti~~on from theS-HTr,, 5-HT,, and 5-FIT,, subtypes. N-v+Schm iedebergs Arch. Pharmac, 332: 8-15.Cocks T. M. and Angus J, A. (1983) Endotheliumdependent relaxation of coronary arteries by nor-adrenahne and serotonin Nat w e 305: 627-630.Cohen M. L, and W~ttena~r L. A. (1985) Re~a~on~i~between serotonin and tryp~m~ne receptors in the ratstomach fundus. J. Pharmac. exp. Ther. 233: 75-79.Cohen M. L., Mason N., Wiley K. S. and Fuller R. W.(I983a) Further evidence that vascular serotonin recep-tors are of the S-HT, type. &u&em. Pharmac. 32:567-570.Cohen R. A., ShePherd J. T. and Vanbautte P. M.(~9~3b~ 5-Hydrox~~~jne can mediate ando~l~~-

dependent relaxation ofcoronaryarteries. Am . J. Physiol.24% HlOY7-HlOSO.Colpaert F. C. and Janssen P. A. J. (1983) The head twitchresponse to in~a-~~ton~ apron of %hydroxy-t~toph~ in the rat: Antagonist effects of mzr.rorted5-hydroxytryptarnine antagonists and of pirenJ&one, anLSD antagonist. Neurauharmacoloav Z: 993%1OW .Corm P. JT and Sanders-Bush I?,- (1985) Serotonin-stimulated ~hospho~nositide turnover: mediation by theS, binding site in rat cerebral cortex but not in subcorticalregions. J. Pharm ac. exp. Ther. 234~ 195-203.Connor H. E., Feniuk W.: Humphrey P. P, A. and PerrenM. J. (1986) ~~r~xa~do-~~tamine is a selectiveagonist at S-HT receptors med&rg vasodikatian andtachycardia in anaestbetized cats. Br. J. Pharmac. 87:417-426.Cox B. and Ennis C. (1982) Characterisation of~hydroxyt~t~~rgi~ autoreceptors in the rat bypo-thahmus. J. P&m. pharmac. 34~ 438-44f.Curro F. A., Greenberg S., Verbeuren T. J. and VanhoutteP. M. (1978) Interaction between alpha adrenernic andserotonergic activation of canine &phenous v&s. J.Pbarmae. exjz Tkr. 20% 936-949.Dalton D. W.; Feniuk W. and Humphrey P. P. A, (1985)An analysts of the cardiovascular effwts of Shydroxptryptarnine in conscious DOCA-salt hypertensive rats.Br. J. P~ar~c. 86: 595P.

De Clerck F., Xhonneux B., Leysen J. and Janssen P. A, J.(1984) The involvement of 5-HT,-recentor sites in the

Davies M., Roberts M. H. T, and Wi~k~~on L. S. ($985)ESbcts of intravenous ketanserin, methysergide and MDL72222 on responses to iontophoretically applied .5HT inthe rat brainstem. Br. 1. Pharmac. 85: 255P.

adVafiQn Of CHf phSe&~_ Tag. J&S:3: 305-321.Dompert W, U., GIaser T. and Tiaber J. (1985) %-TV% Q7821: ide~ti~~tion of 5-HT, binding sites as target for anovel putative anxiolytic. Nauny n-Schmiedebergs Arch.Pharmae. 328: 467~70.Donatsch P., Engel G., Richardson B. F. and Stadler P. A.(L984) ICS 205-930: a highly selective and potent antago-nist at peripheral neuronal S-hydroxytryptamiue (S-HT)receptors. i3r. J. Pars . 8k 34P,EngeJ G., G6thert M., M~~~er-~hw~inj~ E., Sehhcker E,,Sistonen L. and Stadfer P. A. (19831 Evidence forcommon pharmacological properties of [sHj%hydroxy-tryptamine binding sites, presynaptic S-hydroxy-tryptamine autoreceptors in CNS and inhibitory pre-synaptic 5-byd~x~~~~e receptors on sympathetic

nerves- ~~~~*~~~~~r~~ Arch. P#lirr?&re. 324:116-124~ .Engel G., G%bert M., Royer D., S&licker E. and Hiltenbrand K, (1985) Identity of inhibitory presynaptie5-hydroxytryptamine (5-HT) autoreceptors in the ratbrain cortex v&h .%HT,, binding sites. ~~~~-S&mie&&er~s AT& Pharmac. 33% l-7.Engel G,, Roy& D., Kafkman H. 0. and Wick M. B, (1984)~dentifi~t~on of 5-HTs-receptors on ~o~tud~~ muscleof the gninea pig ileum. f. Req. i&s. 4: 113-126.Engef G., Hoyer D., Kafkman H. 0. and Wick M B. (~9~~~Pha~a~~o~~a~ similarity between the 5-HT D-receptoron the guinea-pig ileum and the 5-HT, binding site. Br.J. Pharmac. 84: 106P.Ennis C., Kemp J. D. and Cox B. (1981) Characterisationof inhibitor ~-b~roxyt~~t~~~e receptors that modu-Iate dopamine &ease in the striatum. f. ~~?~c~e~. 3s:15~~~52fl.Feniuk W. (1984) An analysis of ~-hydroxyt~y~tami~ereceptors mediating contraction of isolated smoothmuscle. ~e~~~~~~~~log~ 23~ l46?-I472Feniuk W., Humphrey P. P. A. and Watts A. D. (1979)Presynaptic inhibitory action of 5hydroxytryptamine indog isolated saphenous vein. Br. J. Pharmac. iR 247-254.Fe&k W., Humphrey P. P. A. and Watts A. D. (1981)


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574 P. B. BRADLEYt al .Further characterisation of pre- and post-junctional re-ceptors for 5-hydroxytryptamine in isolated vasculature.Er. J. Phnrmac. 73: 191P-192P.Feniuk W., Humphrey P. P. A. and Perren M. J. (1982)Tryptamine-induced vasopressor responses in pithed ratsare not predominantly mediated via S-hydroxytryptaminereceptors. Br. J. Pharmac. 77: 521P.Feniuk W., Humphrey P. P. A. and Watts A. D. (1983)5-Hydroxytryptamine-induced relaxation of isolatedmammafian smooth muscle. Eur. J. Pharmac. 96: 71-78.Feniuk W., Humphrey P. P. A. and Watts A. D. (1984)5-Carboxamidotryptamine+a potent agonist at5-hydroxytryptamine receptors mediating relaxation. Br.J. Pharmac. 82: 209P.Feniuk W., Humphrey P. P. A., Perren M. J. and WattsA. D. (I985a) A comparison of S-hydroxyt~p~minereceptors mediating contraction in rabbit aorta and dogsaphenous vein. Evidence for different receptor typesobtained by use of selective agonists and antagonists. Er.J. Phurmac. 86: 697-704.

Feniuk W., Humphrey P. P. A. and Hunt A. A. E. (198Sb)The haemodynamic profile and mechanism of the hypo-tensive action of S-carboxamidotryptamine in consciousdogs. Br. J. Pharmac. 85: 31OP.Forster C. and Whalley E. T. (1982) Analysis of the5-hydroxyt~ptamine-indu~d contraption of the humanbasilar arterial strip compared with the rat aortic strip invit ro. Nauny n-Schmiedebergs Arch. Pharmac. 319: 12-17.Fozard J. R. (1982) Mechanism of the hypotensive effect ofketanserin. J. Cardiovasc. Pharmac. 4: 829-838.Fozard J. R. (1983a) Functional correlates of S-HT, recog-nition sites. Trends Pharmac. Sri. 4: 288-289.Fozard J. R. (1983b) Differences between receptors for5-hydroxytryptamine on autonomic neurones revealed bynor-( -)-cocaine. J. Auton. Pharmac. 3: 21-26.Fozard J. R. (1984af Neuronal 5-HT receptors in theperiphery. ~europharmaco~ogy 23: 1473-1486.Fozard J. R. (1984bl MDL 72222. a ootent and highly

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Proposals for the Classification and Nomenclature of Functional Receptors for Hydroxytryptamine

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