L‐683,877: Pharmacological profile of a novel 5‐HT3 receptor antagonist

Abstract

AbstractThe 5‐HT3 receptor antagonist properties of the novel compound L‐683,877 (−) (2′‐(1‐methyl‐1H‐indol‐3‐yl)‐)spiro(1‐azabicyclo[2.2.2]octane‐3,5′(4′H)‐oxazole) have been characterised in vitro and in vivo. In radioligand binding studies, L‐683,877 displaced [3H]quaternized ICS 205–930 binding to membranes of rat cortex with a pKi of 8.71. L‐683,877 was essentially inactive (pKi<5) at 5‐HT1A, 5‐HT1B, 5‐HT1C, 5‐HT1D, 5‐HT2, and dopamine D1 and D2 binding sites. In the rat isolated vagus nerve and superior cervical ganglion (SCG) preparations, L‐683,877 antagonized 5‐HT3 agonist‐induced depolarizations with apparent pKB values of 9.30 and 8.25, respectively. Similarly L‐683,877 antagonized the positive chronotropic effects of 5‐HT in the isolated rabbit heart preparation (apparent pKB 10.10). In the anaesthetized rat, L‐683,877 (10–100 μg kg−1 i.v.) antagonized the Bezold Jarisch reflex evoked by 5‐HT; at a dose of 10 μg kg−1 i.v. L‐683,877 caused a twofold shift in the dose response curve. The retching and vomiting response induced in the ferret by cisplatin (10 mg kg−1 i.v.), was markedly attenuated by L‐683,877 (0.1 mg kg−1 i.v. and p.o.) and completely prevented by higher doses (10 mg kg−1 i.v. and p.o.). These data indicate that L‐683,877 is a potent and selective 5‐HT3 receptor antagonist.