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. 2009 Aug 1;615(1-3):1-9.
doi: 10.1016/j.ejphar.2009.04.035. Epub 2009 May 3.

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

Raymond G Booth  1 , Lijuan Fang, Yingsu Huang, Andrzej Wilczynski, Sashikala Sivendran
Affiliations

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

Raymond G Booth et al. Eur J Pharmacol. .

Abstract

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.

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Figures

Fig. 1
Fig. 1
Structures of 1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT) stereoisomers.
Fig. 2
Fig. 2
Representative saturation binding curves for serotonin 5-HT2 receptor radioligands used to calculate Bmax ± SEM. (pmol/mg protein) and Kd ± S.E.M (nM) values.

  1. (A) [3H]-Ketanserin labeled 5-HT2A receptors; Bmax = 1.73 ± 0.11, Kd = 0.80 ± 0.03.

  2. (B) [3H]-Mesulergine labeled 5-HT2B receptors; Bmax = 1.13 ± 0.39, Kd = 5.19 ± 0.36.

  3. (C) [3H]-Mesulergine labeled 5-HT2C receptors; Bmax = 8.37 ± 0.15, Kd = 0.88 ± 0.03.

Fig. 3
Fig. 3
Representative concentration–response curves for PAT isomer displacement of 5-HT2 receptor radioligands from 5-HT2A (A), 5-HT2B (B), and 5-HT2C (C) receptors. Ki and nH values are summarized in the Table.
Fig. 4
Fig. 4
Representative concentration–response curves for serotonin (closed squares) and (−)-trans-PAT (closed circles) activation of PLC/[3H]-IP formation in clonal cells expressing 5-HT2C receptors. Single concentration effect of (−)-trans-PAT at 5-HT2A (open triangles) and 5-HT2B (open squares) receptors also is shown. EC50 and nH values are given in the text.
Fig. 5
Fig. 5
Representative graphed data for (−)-trans-PAT competitive antagonism of serotonin activation of 5-HT2A (A) and 5-HT2B (B) receptors.
Fig. 6
Fig. 6
Representative graphed data for (−)-trans-PAT inverse agonist activity at serotonin 5-HT2A (A)and 5-HT2B (B) receptors.
Fig. 7
Fig. 7
Molecular models of the 5-HT2A (A), 5-HT2B (B), and 5-HT2C (C) receptors with (−)-trans-PAT docked at the putative binding pocket.
Fig. 7
Fig. 7
Molecular models of the 5-HT2A (A), 5-HT2B (B), and 5-HT2C (C) receptors with (−)-trans-PAT docked at the putative binding pocket.
Fig. 7
Fig. 7
Molecular models of the 5-HT2A (A), 5-HT2B (B), and 5-HT2C (C) receptors with (−)-trans-PAT docked at the putative binding pocket.
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