5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivatives.
Metoclopramide (1) is a gastric motility stimulant and a weak dopamine and 5-HT3 receptor antagonist. Conformational restriction of the (diethylamino)ethyl side chain of 1 in the form of the azabicyclic tropane gave 3, a very potent gastric motility stimulant and 5-HT3 receptor antagonist but devoid of significant dopamine receptor antagonist properties. Subsequent alteration of the aromatic nucleus led to the identification of indazoles 6a-h, and 1- and 3-indolizines 7b-d and 8, and imidazo[1,5-alpha]pyridines 9 and 10, as potent 5-HT3 receptor antagonists devoid of either dopamine antagonist or gastric motility stimulatory properties. Further conformational restriction of the side chain identified quinuclidine 11 and isoquinuclidine 12 as potent 5-HT3 receptor antagonists which mimic the distorted chair conformation of the tropane with, in the case of 11, the N-methyl group axial. From these series, 6g (BRL 43694) was found to be both potent and selective and has been shown to be a very effective antiemetic agent against cytotoxic drug induced emesis both in the ferret and in man.
Bermudez
J
J
Beecham Pharmaceuticals Research Division, Harlow, Essex, England.
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D000818:Animals; D000932:Antiemetics / Q000138:chemical synthesis; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D005289:Ferrets; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D007212:Indolizines / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000138:chemical synthesis*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000932:Antiemetics; D002264:Carboxylic Acids; D007191:Indazoles; D007202:Indicators and Reagents; D007212:Indolizines; D011720:Pyrazoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin