SC-53606, A POTENT AND SELECTIVE ANTAGONIST OF 5-HYDROXYTRYPTAMINE-4 RECEPTORS IN ISOLATED RAT ESOPHAGEAL TUNICA MUSCULARIS MUCOSAE

hyl]-6-chloroimi-dazo[1,2-a]pyridine-8-carboxamide hydrochloride (SC-5 3606) acts as an antagonist of 5-hydroxytryptamine4 (5-HT4) receptor-m ediated relaxation of carbachol-induced contractions in rat esophageal tunica muscular mucosae, but does not possess 5-HT4 agonist activity. SC-53606 demonstrated a pA2 Value against 5-HT in this tissue of 7.91 +/- 0.08 (K(i) = 12.3 +/- 1.17 nM). Similar pA2 values of 7.68 +/- 0. 06, 7.67 +/- 0.06 and 7.63 +/- 0.05 were determined for the synthetic 5-HT4 receptor agonists SC-53116, 5-methoxytryptamine and renzapride, respectively. In addition, slopes of Schild plots for antagonism of th ese four agonists by SC-53606 were 1.07 +/- 0.02, 0.98 +/- 0.03, 1.04 +/- 0.02 and 0.96 +/- 0.06, respectively, and did not deviate from uni ty. The pA2 values for 5-HT4 antagonism against 5-HT were determined t o be 6.80 +/- 0.09 for tropisetron and 7.36 +/- 0.08 for 2-methoxy-4-a mino-S-chlorobenzoic acid-2-(diethylamino)ethyl ester SDZ 205-557), in dicating that SC-53606 is more a potent 5-HT4 antagonist than either o f the reference antagonists. Radioligand binding studies also demonstr ated that SC-53606 is a selective antagonist with more affinity for 5- HT, than for other 5-HT receptors. Displacement of radioligand binding from 5-HT, and 5-HT2 receptors by SC-53606 was less than 50% at a 10 muM concentration. Similarly, SC-53606 displayed little binding affini ty at alpha1, alpha2 and beta adrenergic, dopamine1, dopamine2 and mus rarinic cholinergic receptors. The K for binding to rat cortical 5-HT3 receptors was 259 +/- 28 nM, which was 21 times less than the pA2 con centration in the rat esophageal tunica muscular mucosae assay. SC-536 06 was also a weaker antagonist at 5-HT3 receptors in guinea pig ileum than either tropisetron or SDZ 205-557 (IC50 values of 40 muM, 0.05 m uM and 10 muM, respectively, against 10 muM of 2-methyl-5-HT). These r esults demonstrate that SC-53606 is a potent antagonist at the 5-HT4 r eceptor and possesses selectivity that makes it a useful pharmacologic al tool for studying 5-HT4 receptors.