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DOI: 10.1039/A903328I (Paper) Reference Section for: J. Chem. Soc., Perkin Trans. 1, 1999, 2713-2723

Synthesis and pharmacological profile of a series of 2,5-substituted-N,N-dimethyltryptamine derivatives as novel antagonists for the vascular 5-HT1B-like receptor

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Gerard P. Moloney, Graeme R. Martin, Neil Mathews, Heather Hobbs, Susan Dodsworth, Pang Yih Sang, Cameron Knight, Miles Maxwell and Robert C. Glen

Abstract

The coronary 5-HT1B-like receptor has been implicated in vasospasm and it is postulated that a 5-HT1B-like antagonist may block the detrimental action of 5-HT whilst not interfering with normal blood vessel function. The synthesis and pharmacological profile of a novel series of 2-(N-heteroaryl)carboxamido-5-substituted-N,N-dimethyltryptamine derivatives as silent (as judged by the inability of angiotensin II to unmask 5-HT1B-like receptor mediated agonist activity in the rabbit femoral artery), competitive and selective 5-HT1B-like receptor antagonists is described. Modifications to the 2-carboxamido sidechain as well as the 5-ethylene linked heterocycle are explored. N-Furfuryl-5-[2-(N-phthalimido)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide (34) was discovered which fulfilled our in vitro selection criteria and which had a favourable pharmacokinetic profile. Compound 34 showed good affinity (pKB = 7.38) for the vascular 5-HT1B-like receptor and greater than 125 fold selectivity over α1-adrenoceptor affinity. The selectivity of 34 and related compounds for the 5-HT1B-like receptor over other receptor subtypes is discussed and a mode of binding for this class of compound to a pharmacophore model is proposed.

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