A NOVEL CLASS OF 5-HT2A RECEPTOR ANTAGONISTS - ARYL AMINOGUANIDINES

Local delivery of serotonin (5-HT) produces a rapid edematous response in soft tissues via increased fluid extravasation which is prevented by 5-HT2 antagonists such as ketanserin or mianserin. Here we report t he effects of a new class of aminoguanidine 5-HT2 antagonists, with re lative selectivity for 5-HT2A receptors which are potent inhibitors of 5-HT-induced paw edema in the rat. Radioligand binding studies with I -125 DOI On human 5-HT2A and 5-HT2C receptors and with H-3-5-HT on hum an 5-HT2B receptors demonstrated that, LY314228, and LY320954 displaye d some selectivity for the 5-HT2A receptor. When compared to binding a t other 5-HT2 receptor subtypes, LY314228 had an 18.6-fold greater aff inity for the 5-HT2A site over the 5-HT2B site, and 2.6 fold greater a t the 5.HT2C site. LY320954 displayed similar preference for 5-HT2A si tes. Both compounds also inhibited 5-HT-induced paw swelling in rats, with ED(50)'s of 6.4 and 4.8 mg/kg (for LY314228 and LY320954, respect ively). These studies offer evidence for a novel class of pharmacophor es for the 5-HT2 receptor family which show greater relative affinitie s for the 5-HT2A receptor subclass.