TY - JOUR T1 - Analysis of serotonergic mechanisms underlying benzamide-induced gastroprokinesis. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 501 LP - 507 VL - 259 IS - 2 AU - M D Linnik AU - B T Butler AU - R R Gaddis AU - N K Ahmed Y1 - 1991/11/01 UR - http://jpet.aspetjournals.org/content/259/2/501.abstract N2 - Serotonin (5-HT) receptors in the myenteric plexus mediate contractility in vitro and may regulate gastric emptying in vivo. This report examines the pharmacology of three benzamides, ML-1035 (4-amino-5-chloro-2-[2-(methylsulfinyl)-ethoxy]-N-[2- (diethylamino)ethyl]-benzamide hydrochloride), metoclopramide and cisapride, in studies which address the serotonergic mechanisms underlying benzamide-induced gastroprokinesis. All three compounds had high affinity at the 5-HT3 receptor as they displaced the 5-HT3 antagonist [3H]GR65630 from cortical membranes (Ki = 156, 232 and 1711 nM for ML-1035, metoclopramide and cisapride, respectively) and blocked the 5-HT-induced Bezold-Jarisch reflex, although cisapride was much less active in this experiment. Receptor selectivity was also compared at 5-HT1, 5-HT2, and dopamine D2 receptors in which no displacement was observed that was common to all agents. All benzamides elicited a 5-HT4-like agonist response as they enhanced field-stimulated neurogenic contractions in ileum (EC50 = 1.4, 1.6 and 0.013 microM for ML-1035, metoclopramide and cisapride, respectively). ICS 205-930, a proposed 5-HT4 antagonist, competitively antagonized this response for ML-1035 (Kb = 1.6 microM) whereas atropine blocked the twitch response and any additional responses to ML-1035. In vivo, ML-1035 and metoclopramide increased gastric emptying (IC50 = 0.87 and 3.09 mg/kg i.p., respectively). Thus, the benzamides activate a 5-HT4 receptor in the ileum which increases cholinergic contractions and may be one mechanism by which these agents increase gastric emptying. ER -