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Issue 19, 1999
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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

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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Article information


J. Chem. Soc., Perkin Trans. 1, 1999, 2713-2723
Article type
Paper

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

G. P. Moloney, G. R. Martin, N. Mathews, H. Hobbs, S. Dodsworth, P. Yih Sang, C. Knight, M. Maxwell and R. C. Glen, J. Chem. Soc., Perkin Trans. 1, 1999, 2713
DOI: 10.1039/A903328I

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