Lipid Trolling to Optimize A₃ Adenosine Receptor-Positive Allosteric Modulators (PAMs).

ABSTRACT: A₃ adenosine receptor (A₃AR) positive allosteric modulators (PAMs) (2,4-disubstituted-1H-imidazo[4,5-c]quinolin-4-amines) allosterically increase the E_max of A₃AR agonists, but not potency, due to concurrent orthosteric antagonism. Following mutagenesis/homology modeling of the proposed lipid-exposed allosteric binding site on the cytosolic side, we functionalized the scaffold, including heteroatom substitutions and exocyclic phenylamine extensions, to increase allosteric binding. Strategically appended linear alkyl-alkynyl chains with terminal amino/guanidino groups improved allosteric effects at both human and mouse A₃ARs. The chain length, functionality, and attachment position were varied to modulate A₃

SUBMITTER: Pradhan B 

PROVIDER: S-EPMC11636968 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature