γ-Mangostin, a novel type of 5-hydroxytryptamine 2A receptor antagonist

Abstract

γ-Mangostin, purified from the fruit hull of the medicinal plant Garcinia mangostana caused a parallel rightwards shift of the concentration/response curve for the contraction elicited by 5-hydroxytryptamine (5-HT) in the rabbit aorta (pA₂ = 8.2) without affecting the contractile responses to KCl, phenylephrine (α₁) or histamine (H₁). The perfusion pressure response of rat coronary artery to 5-HT (5-HT_2A) was reduced concentration dependently by γ-mangostin (IC₅₀ = 0.32 μM). 5-HT amplified, ADP-induced aggregation of rabbit platelets (5-HT_2A) was inhibited by γ-mangostin (IC₅₀ = 0.29 μM), whereas that induced by thrombin was not affected, nor did γ-mangostin affect 5-HT-induced contraction of the guinea-pig ileum (5-HT₃)in the presence of 5-HT₁, 5-HT₂ and 5-HT₄ receptor antagonists. Furthermore, 5-HT-induced contraction of the rat fundus (5-HT_2B) and 5-HT-induced relaxation of the rabbit aorta in the presence of ketanserin (5-HT₁) and carbachol-induced contraction of the guinea-pig ileum (muscarinic M₃) were not affected by γ-mangostin (5 μM). γ-Mangostin inhibited [³H]spiperone binding to cultured rat aortic myocytes (IC₅₀ = 3.5 nM). The K _d for [³H]spiperone binding was increased by γ-mangostin (3 nM) from 11.7 to 27.4 nM without affecting B _max. These results suggest that γ-mangostin is a novel competitive antagonist, free from a nitrogen atom, for the 5-HT_2A receptors in vascular smooth muscles and platelets.