Synthesis of 2-amino-3-heteroaroylthiophenes and evaluation of their activity as potential allosteric enhancers at the human A(1) receptor

2-Amino-3-benzoylthiophenes are allosteric enhancers of agonist binding to the adenosine A1 receptor. New compds. bearing an heteroaroyl instead of the benzoyl moiety at the 3-position of the thiophene were synthesized. The Ph ring was replaced with heterocycles that possess heteroatoms able to form hydrogen bonds (2-furanyl, 2-benzofuranyl, 2-pyridinyl) or with a thienyl moiety as isostere of the Ph ring (2-thienyl, 3-thienyl and 5-halo-2-thienyl). The effect of several alkyl substituents at positions 4 and 5 of the thiophene ring to increase enhancer activity was detd. The ability of the new mols. to reduce the cAMP content in CHO cells expressing the human adenosine A1 receptor was evaluated. Compds. with hydrogen bond-forming heteroatoms did not show significant activity as allosteric enhancers. On the other hand, compds. with an unsubstituted thienyl moiety as replacement for the Ph ring were nearly as efficacious as PD 81,723, the prototypical A1 allosteric enhancer. Alkyl substituents at positions 4 and 5 of the thiophene ring were tolerated while a substituted piperidine ring was not tolerated. It was concluded that hydrogen bonds could not be formed in the domain of the receptor that accommodates the Ph ring of 2-amino-3-benzoylthiophene derivs., indicating that this domain is hydrophobic.