CHEM E-120 Harvard University Extension School Spring 2011 Hypothalamus-Pituitary-Adrenal Neuroendocrine System HPA Axis 2/16/111CHEM E-120.

CHEM E-120Harvard University Extension School

Spring 2011

Hypothalamus-Pituitary-Adrenal Neuroendocrine SystemHPA Axis

2/16/11 1CHEM E-120

2

HPA Axis – Neuroendocrine System

Hypothalamus Pituitary Gland Adrenal Gland (kidney)CRH ACTH

CortisolPrimary stress hormone

CRF - corticotrophin releasing factor (CRH)ACTH - adrenocorticotropic hormoneCRH1 and CRH2 GPCR receptors localized in pituitary, cortex, amyglada, LC, and hypothalamusCortisol binds to glucocorticoid receptors (GR) and mineralocorticoid receptor (MR)Cortisol negative feedback action on the production of cortisol

HPA axis is the major pathway by which stress is effected

ACh +5-HT +NE +/-GABA -

Trends in Neuroscience 2008, 31, 464Neurochem Res 2008, 33, 691

AVP – arginine vasopressin

2/16/11 CHEM E-120

3

CRFCRF - corticotrophin-releasing factor (corticotrophin-releasing hormone, CRH)41 amino acid neuropeptide that initiates and regulates the HPA-axisresponse to stress

CRF1 receptor has been implicated in anxiety and depressionCRF antagonists are anxiolytic in animal modelsHyperactivity of hypothalamic CRF neurons, overproduction of CRFDecreased levels of CRF1 in frontal cortex of depressed patientsSuggestion of CRF1 desensitizationNeural locations allow it to interact with multiple neurotransmitter systemsPTSD - increased levels of CRFMice overexpressing CRF have “high anxiety” phenotypeCFR1 knockout mice display behavioral phenotypes of low anxietyOverexpression of CRF in mice increases anxiety behaviourRats - administration of CRF produces anxiogenic state antagonized by DMP696 (CRF1 antagonist)CFR increases startle response in mice that is antagonized

CNS & Neurological Disorders - Drug Targets 2007, 6, 163-182Neurochem Res 2008, 33, 691

2/16/11 CHEM E-120

Cortisol – Endocrine Hormone

Major depression elevated serum levels of cortisolFunctional and expression changes of glucocorticoid receptors (GR) Antidepressants increase GR expression, function, and feed-back inhibitionFlattened diurnal rhythm (normal 16 μg/100 mL @ 8am, 4 μg/100 mL @4 pm)

Biosynthetic pathway in the adrenal gland

2/16/11 4CHEM E-120

Comparison of the MR and GR Receptors

Mineralocorticoid Receptor• High affinity for cortisol• Expression in hippocampus

and amygdala• Occupied when CORT is low and

when CORT is high• Agonist: Aldosterone• Antagonist: RU26752

Glucocorticoid Receptor• Low affinity for cortisol• Expression in hippocampus,

amygdala, hypothalamus, brain stem, cortex, pituitary

• Occupied when CORT is high• Agonist: Dexamethasone• Antagonist: RU38486

MR thought to mediate tonic control of cortisol

cortisol Kd < 10-9 cortisol Kd ~ 10-8

Members of nuclear receptor superfamily – associated with heat-shock protein, when activated bind to specific DNA recognition sequences of target gene promoters, called hormone response elements

2/16/11 5CHEM E-120

Medication Development Based on HPA Axis

Antidepressants may down regulate p-glycoprotein in the BBB increasing concentrationof cortisol in CNS and re-equilibrate a faulty HP circuit. pGP actively transports cortisol out of the CNS.

Inhibition of cortisol biosynthesis – aminoglutehimide (Cytadren), metyrapone, ketoconazolecurrent inhibitors have high toxicity and have multitude side-effects

GR antagonists – block action of excess cortisol, up-regulate GR expression (reinstall negative feedback loop)

RU486 (Corcept) failed in Phase III trial, all are selective for GR versus MR but also bind toprogesterone receptor (PR).

CRH antagonists – block the CRF-mediated release of ACTH from the pituitary gland reducing the production of cortisol

R121919 (Neurocrine/Janssen) showed positive antidepressant and anoxyltic effects in a20 patient clinical trial (Journal of Psychiatric Research 2000, 34, 171) but drug-induced reversible increases in liver enzymes were found.

2/16/11 6CHEM E-120

Journal of Psychiatric Research 2000, 34, 17Effects of the high-affnity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated.

“…suggesting that a complete blockade ofthe peripheral stress hormone system was unlikely……basal corticotrophic activity is independent from CRH.

2/16/11 7CHEM E-120

Cortisol Levels on Awakening

no statistical difference

2/16/11 8CHEM E-120

Night Cortisol Levels

AUC calculation – significant differences vs control

2/16/11 9CHEM E-120

Bioorganic & Medicinal Chemistry Letters 2010, 1905 (BMS)

2/16/11 10CHEM E-120

11

CRF Antagonists - Pfizer

CP-316311 CP-376395

CP-316311Phase 2 depressionJMC 2008, 51, 1377

CP-376395JMC 2008, 51, 1385

pKa 3.6∼solubility pH 2 = 3 μg/mLsolubility pH 7 = 0.2 μg/mL

pKa 6.9solubility pH 2.4 = 5.4 mg/mLsolubility pH 7 = 0.2 μg/mLgreater bioavalibility

2/16/11 CHEM E-120

CRF Antagonists - BMS

2/16/11 12CHEM E-120

2/16/11 13CHEM E-120