GAMMA-MANGOSTIN, A NOVEL TYPE OF 5-HYDROXYTRYPTAMINE 2A RECEPTOR ANTAGONIST

gamma-Mangostin, purified from the fruit hull of the medicinal plant G arcinia mangostana caused a parallel rightwards shift of the concentra tion/response curve for the contraction elicited by 5-hydroxytryptamin e (5-HT) in the rabbit aorta (pA(2) = 8.2) without affecting the contr actile responses to KCl, phenylephrine (alpha(1)) or histamine (H-1). The perfusion pressure response of rat coronary artery to 5-HT (5-HT2A ) was reduced concentration dependently by gamma-mangostin (IC50 = 0.3 2 mu M). 5-HT amplified, ADP-induced aggregation of rabbit platelets ( 5-HT2A) was inhibited by gamma-mangostin (IC50 = 0.29 mu M), whereas t hat induced by thrombin was not affected, nor did gamma-mangostin affe ct 5-HT-induced contraction of the guinea-pig ileum (5-HT3) in the pre sence of 5-HT1, 5-HT2 and 5-HT4 receptor antagonists. Furthermore, 5-H T-induced contraction of the rat fundus (5-HT2B) and 5-HT-induced rela xation of the rabbit aorta in the presence of ketanserin (5-HT1) and c arbachol-induced contraction of the guinea-pig ileum (muscarinic M-3) were not affected by gamma-mangostin (5 mu M). gamma-Mangostin inhibit ed [H-3]spiperone binding to cultured rat aortic myocytes (IC50 = 3.5 nM). The K-d for [H-3]spiperone binding was increased by gamma-mangost in (3 nM) from 11.7 to 27.4 nM without affecting B-max. These results suggest that gamma-mangostin is a novel competitive antagonist, free f rom a nitrogen atom, for the 5-HT2A receptors in vascular smooth muscl es and platelets.