Synthesis and serotonergic activity of a series of 2-(N-benzyl)carboxamido-5-substituted-N,N-dimethyltryptamine derivatives: novel antagonists for the vascular 5-HT1B-like receptors

The synthesis and vascular 5-HT1B-like receptor activity of a novel series of 2-(N-benzyl)carboxamido-5-substituted-N,N-dimethyltryptamine derivatives is described. Modifications to the 5-ethylene linked heterocycle are explo red. Compounds such as N-benzyl-5-[2-(phthalimido)ethyl]-3-[2-(dimethylamin o)ethyl]-1H-indole-2-carboxamide 22 (pK(B) = 7.33), the 2-aminobenzyl analo gue 24 (pK(B) = 7.19), which both contain a phthalimide group, and N-benzyl -5-[2-(1-benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-3-[2-(dimethylamino)ethyl ]-1H-indole-2-carboxamide 81 (pK(B) = 7.05), which incorporates an N-benzyl hydantoin moiety, have good 5-HT1B-like affinity and indicate that there ma y be a hydrophobic binding pocket within the vascular 5-HT1B-like receptor previously not considered. Compounds including N-benzyl-3-[2-(dimethylamino )ethyl]-5-[2-(2,4-dioxo-1,3-thiazolidinyl)ethyl]-1H-indole-2-carboxamide 39 (pK(B) = 7.35) and the dimethyl analogue 46 (pK(B) = 7.48) which contain a 2,4-thiazolidinedione moiety have good vascular 5-HT1B-like receptor affin ity and show that the sulfur atom is well tolerated. Compound 61 which incl udes a methylsulfonyl substituent on the 1-nitrogen of the hydantoin ring s ystem has the highest recorded 5-HT1B-like affinity for this series (pK(B) = 7.54) and it is proposed that this functional group can interact with a s econdary hydrogen bonding region within the receptor. Compounds 22, 24, 39, 46, 61 and 81 also exhibited good selectivity over the alpha(1)-adrenocept ors. The most selective compound from this series is 46 which contains a 5, 5-dimethylthiazolidine-2,4-dione group and which is 66-fold selective over the alpha(1)-adrenoceptors. This finding is consistent with the previous di scovery that 5,5-dimethyl substitution on the hydantoin group in a related series of compounds afforded superior selectivity for 5-HT1B-like receptors over alpha(1)-adrenoceptors and other 5-HT receptors, in particular 5-HT2A receptors, relative to unsubstituted hydantoin analogues. The selectivity of these compounds for the vascular 5-HT1B-like receptor is discussed. Stru cture-activity relationship indicated a significant steric requirement of t he 5-HT1B-like receptor subtype. Potential modes of binding for several of the compounds to a vascular 5-HT1B-like receptor pharmacophore model are al so proposed.