+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

(1R, 3S)-(-)-trans-PAT: a novel full-efficacy serotonin 5-HT2C receptor agonist with 5-HT2A and 5-HT2B receptor inverse agonist/antagonist activity

(1R, 3S)-(-)-trans-PAT: a novel full-efficacy serotonin 5-HT2C receptor agonist with 5-HT2A and 5-HT2B receptor inverse agonist/antagonist activity

European Journal of Pharmacology 615(1-3): 1-9

The serotonin 5-HT(2A), 5-HT(2B), and 5-HT(2C) G protein-coupled receptors signal primarily through G alpha(q) to activate phospholipase C (PLC) and formation of inositol phosphates (IP) and diacylglycerol. The human 5-HT(2C) receptor, expressed exclusively in the central nervous system, is involved in several physiological and psychological processes. Development of 5-HT(2C) agonists that do not also activate 5-HT(2A) or 5-HT(2B) receptors is challenging because transmembrane domain identity is about 75% among 5-HT(2) subtypes. This paper reports 5-HT(2) receptor affinity and function of (1R,3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT), a small molecule that produces anorexia and weight-loss after peripheral administration to mice. (-)-Trans-PAT is a stereoselective full-efficacy agonist at human 5-HT(2C) receptors, plus, it is a 5-HT(2A)/5-HT(2B) inverse agonist and competitive antagonist. The K(i) of (-)-trans-PAT at 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors is 410, 1200, and 37 nM, respectively. Functional studies measured activation of PLC/[(3)H]-IP formation in clonal cells expressing human 5-HT(2) receptors. At 5-HT(2C) receptors, (-)-trans-PAT is an agonist (EC(50) = 20 nM) comparable to serotonin in potency and efficacy. At 5-HT(2A) and 5-HT(2B) receptors, (-)-trans-PAT is an inverse agonist (IC(50) = 490 and 1,000 nM, respectively) and competitive antagonist (K(B) = 460 and 1400 nM, respectively) of serotonin. Experimental results are interpreted in light of molecular modeling studies indicating the (-)-trans-PAT protonated amine can form an ionic bond with D3.32 of 5-HT(2A) and 5-HT(2C) receptors, but, not with 5-HT(2B) receptors. In addition to probing 5-HT(2) receptor structure and function, (-)-trans-PAT is a novel lead regarding 5-HT(2C) agonist/5-HT(2A) inverse agonist drug development for obesity and neuropsychiatric disorders.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 051017979

Download citation: RISBibTeXText

PMID: 19397907

DOI: 10.1016/j.ejphar.2009.04.035

Related references

A novel aminotetralin-type serotonin (5-HT) 2C receptor-specific agonist and 5-HT2A competitive antagonist/5-HT2B inverse agonist with preclinical efficacy for psychoses. Journal of Pharmacology and Experimental Therapeutics 349(2): 310-318, 2014

Inverse agonist activity of sarpogrelate, a selective 5-HT2A-receptor antagonist, at the constitutively active human 5-HT2A receptor. Journal of Pharmacological Sciences 102(2): 189-195, 2006

Effects of the serotonin 5-HT2A/2C receptor agonist DOI and of the selective 5-HT2A or 5-HT2C receptor antagonists EMD 281014 and SB-243213, respectively, on sleep and waking in the rat. European Journal of Pharmacology 553(1-3): 163-170, 2006

Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment. Psychopharmacology 157(2): 180-187, 2001

The role of serotonin-2 (5-HT2) and dopamine receptors in the behavioral actions of the 5-HT2A/2C agonist, DOI, and putative 5-HT2C inverse agonist, SR46349B. Psychopharmacology 213(2-3): 393-401, 2011

Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2c receptor inverse agonist but fails to induce 5-HT2c receptor down-regulation. Psychopharmacology. 136(2): 99-104, Ch, 1998

High-affinity agonist binding correlates with efficacy (intrinsic activity) at the human serotonin 5-HT2A and 5-HT2C receptors: Evidence favoring the ternary complex and two-state models of agonist action. Journal of Neurochemistry 72(5): 2127-2134, 1999

Effects of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist M100907 on nicotine self-administration and reinstatement. Neuropharmacology 62(7): 2288-2298, 2012

Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells. European Journal of Pharmacology 594(1-3): 32-38, 2008

Serotonin 5-HT2A but not 5-HT2C receptor antagonism reduces hyperlocomotor activity induced in dopamine-depleted rats by striatal administration of the D1 agonist SKF 82958. Neuropharmacology 49(3): 350-358, 2005

5-HT2c receptor antagonists, but not a 5-HT2A or 5-HT2B receptor antagonist, attenuate haloperidol-induced catalepsy in rat. British Journal of Pharmacology 125(PROC SUPPL ): 65P, 1998

Receptor binding analysis of the 5 ht2b receptor comparing agonist, partial agonist and antagonist radioligands. Society for Neuroscience Abstract Viewer & Itinerary Planner : Abstract No 641 1, 2002

Agonist and inverse agonist efficacy at human recombinant serotonin 5-HT-1A receptors as a function of receptor:G-protein stoichiometry. Neuropharmacology 36(4-5): 451-459, 1997

Reciprocal regulation of agonist and inverse agonist signaling efficacy upon short-term treatment of the human delta-opioid receptor with an inverse agonist. Molecular Pharmacology 67(1): 336-348, 2004

Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis. Clinical Neuropharmacology 29(2): 80-86, 2006