2-Amino-3-benzoyl thiophenes have been widely reported to act as allosteric enhancers at the A1 adenosine receptor. Their activity can be increased considerably by appropriate substitutions at the 4- and 5-positions of the thiophene ring. Substituent size at the thiophene C-4 position seemed to be a factor closely related to activity, with the 4-neopentyl (2,2-dimethylpropyl) substitution showing the greatest enhanced activity. A wide series of 2-amino-3-aroyl-4-neopentylthiophene derivatives with general structure 3, characterized by the presence of different substituents (bromine, aryl and heteroaryl) at the 5-position of the thiophene ring, have been identified as potent AEs at the A1AR. With only one exception, all of the synthesized compounds proved to be superior to the reference compound PD 81,723 in a functional assay. Derivatives 3p, 3u, 3am, 3ap and 3ar were the most active compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor.
Keywords: 2-Amino-3-benzoylthiophene; 2-chloro-N(6)-cyclopentyladenosine; A(1) adenosine receptor; AE(s); Allosteric modulation; CCPA; CHO; CNS; CsF; ERG; EWG; G protein-coupled receptors; GPCRs; N-bromosuccinimide; NBS; PdCl(2)(DPPF); [(3)H](4-(2-[7-amino-2-(2-furil)[1,2.4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol); [(3)H]1,3-dipropyl-8-cyclopentyl-xanthine; [(3)H]2-chloro-N(6)-cyclopentyladenosine; [(3)H]5-N-(4-methoxyphenylcarbamoyl)amino-8-propyl-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine; [(3)H]CCPA; [(3)H]DPCPX; [(3)H]MRE-3008F20; [(3)H]ZM 241385; [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane; allosteric enhancer(s); cAMP; central nervous system; cesium fluoride; chinese hamster ovary; cyclic adenosine monophosphate; electron-releasing group; electron-withdrawing group; hA(1)AR; human A(1) adenosine receptor.
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