Allosteric modulators for adenosine receptors (ARs) are of an increasing interest and may have potential therapeutic advantage over orthosteric ligands. Benzoylthiophene derivatives (including PD 81,723), 2-aminothiazolium salts, and related allosteric modulators of the A1 AR have been studied. The benzoylthiophene derivatives were demonstrated to be selective enhancers for the A1 AR, with little or no effect on other subtypes of ARs. Allosteric modulation of the A2A AR has also been reported. A3 allosteric enhancers may be predicted to be useful against ischemic conditions. We have recently characterized two classes of A3 AR allosteric modulators: 3-(2-pyridinyl)isoquinolines (e.g. VUF5455) and 1H-imidazo-[4,5- c]quinolin-4-amines (e.g. DU124183), which selectively decreased the agonist dissociation rate at the human A3AR but not at A1 and A2A ARs. DU124183 left-shifted the agonist conc.-response curve for inhibition of forskolin-stimulated cAMP accumulation in intact cells expressing the human A3AR with up to 30% potentiation of the maximal efficacy. The increased potency of A3 agonists was evident only in the presence of an A3 antagonist, since VUF5455 and DU124183 also antagonized, i.e. displaced binding at the orthosteric site, with Ki values of 1.68 and 0.82 μM, respectively. A3AR mutagenesis studies implicated F1825.43 and N2747.45 in the action of the enhancers and was interpreted using a rhodopsin-based A3AR molecular model, suggesting multiple binding modes. Amiloride analogues, SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol- 5(2H)-ylidene)methanamine), and sodium ions were demonstrated to be common allosteric modulators for at least three subtypes (A1, A2A, and A3) of ARs.
adenylate cyclase, g protein-coupled receptors(gpcrs), allosteric enhancers, chemical libraries, binding assays, camp, radioligand, diuretic, mutagenesis
Molecular Recognition Section, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810, USA.