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

•Compounds 3a–d appeared to be more active than PD 81,723 in the functional assay.•None of compounds 3a–aq inhibited antagonist binding at the hA1AR, hA2AR, or hA3AR.•Derivatives 3a–c, 3e and 3n were the most active compounds in binding experiments.

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, tetrahydro-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 3a–c and 3e 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.

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