Synthesis and serotonergic activity of substituted 2,N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N,N-dimethyltryptamine derivatives: Novel antagonists for the vascular 5-HT1B-like receptor

The synthesis and vascular 6-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-ethyle ne-linked heterocycle and to substituents on the 2-benzylamide side chain h ave been explored. Several compounds were identified which exhibited affini ty at the vascular 5-HT1B-like receptor of pK(B) > 7.0, up to 100-foId sele ctivity over alpha(1)-adrenoceptor affinity and 5-HT2A receptor affinity, a nd which exhibited a favorable pharmacokinetic profile. N-Benzyl-3-[2-(dime thylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-in dole-2-carboxamide (23) was identified as a highly potent, silent (as judge d by the inability of angiotensin II to unmask 5-HT1B-like receptor-mediate d agonist activity in the rabbit femoral artery), and competitive vascular 5-HT1B-like receptor antagonist with a plasma elimination half-life of simi lar to 4 h in dog plasma and with good oral bioavailability. The selectivit y 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 rat her than the indole ring. The resulting conformation allows an amine-bindin g site to be occupied by the ethylamine nitrogen and a hydrogen-bonding sit e to be occupied by one of the hydantoin carbonyls. The electronic nature o f the 2,N-benzylcarboxamide aromatic group as well as the size of substitue nts on this aromatic group is crucial for producing potent and selective an tagonists. The structural requirement on the 3-ethylamine side chain incorp orating the protonatable nitrogen is achieved by the bulky 2,N-benzylcarbox amide group and its close proximity to the 3-side chain.