252960-85-3Relevant academic research and scientific papers
Synthesis and serotonergic activity of a series of 2-(JV-benzyl)carboxamido-5-substituted-N,N-dimethyltryptamine derivatives: Novel antagonists for the vascular 5-HT1B-like receptors
Moloney, Gerard P.,Martin, Graeme R.,Mathcws, Neil,Hobbs, Heather,Dodsworth, Susan,Sang, Pang Yih,Knight, Cameron,Maxwell, Miles,Glen, Robert C.
, p. 2699 - 2711 (2007/10/03)
The synthesis and vascular 5-HT,B-like receptor activity of a novel series of 2-(Ar-benzyl)carboxamido-5-substitutedA-4W-dimethyltryptamine derivatives is described. Modifications to the 5-ethylene linked heterocycle are explored. Compounds such as N-benzyl-5-[2-(phthalimido)ethyl]-3-[2-(dimethylamino)ethyl]-l//-indole-2- carboxamide 22 (pA'B = 7.33), tfie 2-aminobenzyl analogue 24 (pA1B = 7.19), which both contain a phthalimide group, and A-4-benzyl-S[2-(l-benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-3-[2-(dimethylamino) ethyl]-l//-indole-2-carboxamide 81 (pATB = 7.05), which incorporates an N-benzylhydantoin moiety, have good 5-HT1B-like affinity and indicate that there may 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-l,3-thiazolidinyl)ethyl]-l// -indole-2-carboxamide 39 (pA1B = 7.35) and the dimethyl analogue 46 (pA1B = 7.48) which contain a 2,4-thiazolidinedione moiety have good vascular 5-HT1B-like receptor affinity and show that the sulfur atom is well tolerated. Compound 61 which includes a methylsulfonyl substituent on the 1-nitrogen of the hydantoin ring system has the highest recorded 5-HT1B-like affinity for this series (pA1B = 7.54) and it is proposed that this functional group can interact with a secondary hydrogen bonding region within the receptor. Compounds 22, 24,39,46,61 and 81 also exhibited good selectivity over the a,-adrenoceptors. 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 a,-adrenoceptors. This finding is consistent with the previous discovery that 5,5-dimethyl substitution on the hydantoin group in a related series of compounds afforded superior selectivity for 5-HT1B-like receptors over a,-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. Structure-activity relationship indicated a significant steric requirement of the 5-HT1B-like receptor subtype. Potential modes of binding for several of the compounds to a vascular 5-HT1B-like receptor pharmacophore model are also proposed. The Royal Society of Chemistry 1999.
