SC-53606, a potent and selective antagonist of 5-hydroxytryptamine4 receptors in isolated rat esophageal tunica muscularis mucosae.

(1-S,8-S)-N-[(hexahydro-1H-pyrrolizin-1-yl)methyl]-6-chloroimi+ ++- dazo[1,2-a]pyridine-8-carboxamide hydrochloride (SC-53606) acts as an antagonist of 5-hydroxytryptamine4 (5-HT4) receptor-mediated 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 (Ki = 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 these 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 unity. The pA2 values for 5-HT4 antagonism against 5-HT were determined to be 6.80 +/- 0.09 for tropisetron and 7.36 +/- 0.08 for 2-methoxy-4-amino-S- chlorobenzoic acid-2-(diethylamino)ethyl ester SDZ 205-557), indicating that SC-53606 is more a potent 5-HT4 antagonist than either of the reference antagonists. Radioligand binding studies also demonstrated that SC-53606 is a selective antagonist with more affinity for 5-HT4 than for other 5-HT receptors. Displacement of radioligand binding from 5-HT1 and 5-HT2 receptors by SC-53606 was less than 50% at a 10 microM concentration. Similarly, SC-53606 displayed little binding affinity at alpha 1, alpha 2 and beta adrenergic, dopamine1, dopamine2 and muscarinic cholinergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

SC-49518 enhances gastric emptying of solid and liquid meals and stimulates gastrointestinal motility in dogs by a 5-hydroxytryptamine4 receptor mechanism.

SC-49518 (N-[exo-(hexahydro-1H-pyrrolizine-1-yl)methyl]-2-methoxy-4- amino-5-chlorobenzamide HCl), a new benzamide gastrointestinal prokinetic compound, was investigated to determine its ability to stimulate gastrointestinal motility in vivo and whether these actions could be mediated by agonist activity at the putative 5-hydroxytryptamine (5-HT)4 receptor. In conscious fasted dogs with strain gauge transducers and myoelectrodes, SC-49518 disrupted gastric and small intestinal migrating motility complex cycling for more than 3.5 hr. It stimulated gastric antral contractile and intestinal myoelectric spike burst activities during the normally quiescent Phase I of the migrating motility complex at doses as low as 0.01 and 0.03 mg/kg i.v., respectively. In a canine model of gastroparesis, SC-49518 reversed completely alpha-2 adrenergically delayed gastric emptying of a solid meal with an ED50 value of 0.1 mg/kg intragastrically and partially reversed delayed emptying of a liquid meal. SC-49518, like 5-HT, cisapride and renzapride, acted as an agonist (EC50 = 6.6 +/- 1.1 x 10(-8) M) at the putative 5-HT4 receptor in rat esophageal tunica muscularis mucosae by relaxing carbachol-induced contractions. SC-49518 was a partial agonist at 5-HT4 receptors, but also blocked high affinity (5-HT4-mediated) responses to 5-HT (10(-9) M to 3 x 10(-7) M) in guinea pig ileum with a pA2 value of 8.39.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative mucosal protective properties of misoprostol, cimetidine, and sucralfate.

Misoprostol, a PGE1 derivative that inhibits gastric acid secretion in rats, was compared with cimetidine and sucralfate in several rat experimental ulcer models. Gastric lesions were produced by aspirin, indomethacin, stress, sodium taurocholate, and ethanol. In all tests, misoprostol (50, 100, and 200 micrograms/kg) and cimetidine and sucralfate (50, 100, and 200 mg/kg) were administered intragastrically. Misoprostol protected against gastric lesions in all five experimental ulcer models at lower than gastric antisecretory doses. Cimetidine protected in the indomethacin, aspirin, and stress models, but only at gastric antisecretory doses, and did not protect against lesion formation in the ethanol and taurocholate models. Sucralfate, over the dose range tested, was not consistently protective in any of the five experimental ulcer models. It is concluded that misoprostol provides gastric mucosal protection against a wide variety of noxious agents by means of a unique mechanism and that reduction of gastric acid secretion is not required, as it is with cimetidine, for the protective effect.