Abstract
The serotonin 5-HT 2A, 5-HT 2B, and 5-HT 2C G protein-coupled receptors signal primarily through G α 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 (1 R,3 S)-(−)- trans-1- phenyl-3-dimethyl amino-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/[ 3H]-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.
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