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

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.