Premium
L‐683,877: Pharmacological profile of a novel 5‐HT 3 receptor antagonist
Author(s) -
Tattersall David,
Newberry Nigel,
Beer Margaret S.,
Rigby Mike,
Gilbert Michael,
Maguire Janet J.,
Mudunkotuwa Nikki,
Duchnowski Mark,
McKnight Alexander T.,
Swain Christopher J.,
Kneen Clare,
Dourish Colin T.
Publication year - 1992
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430250103
Subject(s) - chemistry , endocrinology , chronotropic , medicine , antagonist , agonist , radioligand , 5 ht receptor , retching , pharmacology , receptor , vomiting , serotonin , heart rate , blood pressure
The 5‐HT 3 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 [ 3 H]quaternized ICS 205–930 binding to membranes of rat cortex with a pK i of 8.71. L‐683,877 was essentially inactive (pK i <5) at 5‐HT 1A , 5‐HT 1B , 5‐HT 1C , 5‐HT 1D , 5‐HT 2 , and dopamine D 1 and D 2 binding sites. In the rat isolated vagus nerve and superior cervical ganglion (SCG) preparations, L‐683,877 antagonized 5‐HT 3 agonist‐induced depolarizations with apparent pK B 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 pK B 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‐HT 3 receptor antagonist.