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Synthesis and Serotonergic Activity of Substituted 2, N -Benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)- N , N -dimethyltrypt- amine Derivatives: Novel Antagonists for the Vascular 5-HT 1B -like Receptor

1999; American Chemical Society; Volume: 42; Issue: 14 Linguagem: Inglês

10.1021/jm9706325

1520-4804

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

Nitric Oxide and Endothelin Effects

The synthesis and vascular 5-HT1B-like receptor activity of a novel series of substituted 2,N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N,N-dimethyltryptamine derivatives are described. Modifications to the 5-ethylene-linked heterocycle and to substituents on the 2-benzylamide side chain have been explored. Several compounds were identified which exhibited affinity at the vascular 5-HT1B-like receptor of pKB > 7.0, up to 100-fold selectivity over α1-adrenoceptor affinity and 5-HT2A receptor affinity, and which exhibited a favorable pharmacokinetic profile. N-Benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxamide (23) was identified as a highly potent, silent (as judged by the inability of angiotensin II to unmask 5-HT1B-like receptor-mediated agonist activity in the rabbit femoral artery), and competitive vascular 5-HT1B-like receptor antagonist with a plasma elimination half-life of ∼4 h in dog plasma and with good oral bioavailability. The selectivity of compounds from this series for the vascular 5-HT1B-like receptors over other receptor subtypes is discussed as well as a proposed mode of binding to the receptor pharmacophore. It has been proposed that the aromatic ring of the 2,N-benzylcarboxamide group can occupy an aromatic binding site rather than the indole ring. The resulting conformation allows an amine-binding site to be occupied by the ethylamine nitrogen and a hydrogen-bonding site to be occupied by one of the hydantoin carbonyls. The electronic nature of the 2,N-benzylcarboxamide aromatic group as well as the size of substituents on this aromatic group is crucial for producing potent and selective antagonists. The structural requirement on the 3-ethylamine side chain incorporating the protonatable nitrogen is achieved by the bulky 2,N-benzylcarboxamide group and its close proximity to the 3-side chain.