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-HT1B-like Receptor

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. Th...