Synthesis and biological effects of novel 2-amino-3-(4-chlorobenzoyl)-4- substituted thiophenes as allosteric enhancers of the A1 adenosine receptor

Allosteric enhancers for the A1 adenosine receptor represent a novel and unique drug design strategy to augment the response to endogenous adenosine in a site- and event-specific manner.We have previously investigated a detailed structure-activity relationship study around a wide series of 2-amino-3-aroyl-4-[(4-arylpiperazin-1-yl)methyl]thiophene derivatives as potent allosteric enhancers of the A1 adenosine receptor. In this manuscript we report our investigation on the influence on allosteric enhancer activity of further substitution at the 4-position of the 2-amino-3-(4-chlorobenzoyl)- thiophene system to explore bulk tolerance by replacement of the arylpiperazine moiety with a series of fused indole nuclei corresponding to 1,2,3,4-tetrahydropyrazino[1,2-a ]indole, 1,2,3,4,10,10a-hexahydropyrazino[1,2- a]indole, tet-rahydro- γ-carboline, tetrahydroisoquinoline, spiro-1,3-benzodioxolepiperidine, aliphatic tertiary amine, N-alkylaniline, aryl ether and aryl thioether templates. The 1,2,3,4-tetrahydropyrazino[1,2- a]indole derivatives 3-ec and 3- were the most active compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [3H]CCPA binding to the A1 receptor. This study also shows that it is possible to obtain a good separation between allosteric enhancement and antagonistic activity at the A1 adenosine receptor. © 2013 Elsevier Masson SAS. All rights reserved.