ANTAGONISM BY SB-204070 OF 5-HT-EVOKED CONTRACTIONS IN THE DOG STOMACH - AN IN-VIVO MODEL OF 5-HT4 RECEPTOR FUNCTION

The ability of 5-hydroxytryptamine (5-HT) to evoke contractile activity in the gastric Heidenhain pouch was measured in conscious dogs using a method in which 5-HT4 receptor-antagonist activity can be measured in-vivo. At doses of 5-HT which evoked short-lived measurable responses (5 or 10 mu g kg(-1), i.v.), it was found that this activity was greatly reduced by atropine (100 mu g kg(-1), i.v.), but was unaffected by methysergide, methiothepin, ketanserin (each at 100 mu g kg(-1), i.v.) or granisetron (10 or 100 mu g kg(-1), i.v.). At best SDZ 205-557 2-diethylaminoethyl-[2-methoxy-4-amino-5-chloro] benzoate; 100 mu g kg(-1), i.v.) reduced the action of 5-HT in 4/5 animals and increased it in the other but its effects were variable in magnitude and not consistently maintained. However, the more potent and selective 5-HT4-receptor antagonist SB 204070 (1-butyl-4-piperidinylmethyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylate hydrochloride) dose-dependently antagonized the 5-HT-evoked contractions in all dogs tested. This action was reversible, but long-lasting with an effective half-life of 18.0 h when administered at 1 mu g kg(-1). The estimated ID50 value was 0.55 mu g kg(-1).