Interaction of 1,4-Dihydropyridine and Pyridine Derivatives with Adenosine Receptors:  Selectivity for A₃ Receptors

Abstract

1,4-Dihydropyridine and pyridine derivatives bound to three subtypes of adenosine receptors in the micromolar range. Affinity was determined in radioligand binding assays at rat brain A1 and A2A receptors using [3H]-(R)-PIA [[3H]-(R)-N6-(phenylisopropyl)adenosine] and [3H]CGS 21680 [[3H]-2-[[4-(2-carboxyethyl)phenyl]ethylamino]-5'-(N-ethylcarbamoyl++ +) adenosine], respectively. Affinity was determined at cloned human and rat A3 receptors using [125I]AB-MECA [N6-(4-amino-3-iodobenzyl)-5'-(N-methylcarbamoyl)adenosine]. Structure-activity analysis at adenosine receptors indicated that sterically bulky groups at the 4-, 5-, and 6-positions are tolerated. (R,S)-Nicardipine, 12, displayed Ki values of 19.6 and 63.8 microM at rat A1 and A2A receptors, respectively, and 3.25 microM at human A3 receptors. Similarly, (R)-niguldipine, 14, displayed Ki values of 41.3 and 1.90 microM at A1 and A3 receptors, respectively, and was inactive at A2A receptors. A preference for the R- vs the S-enantiomer was observed for several dihydropyridines at adenosine receptors, in contrast with the selectivity at L-type Ca2+ channels. A 4-trans-beta-styryl derivative, 24, with a Ki value of 0.670 microM at A3 receptors, was 24-fold selective vs A1 receptors (Ki = 16.1 microM) and 74-fold vs A2A receptors (Ki = 49.3 microM). The affinity of 24 at L-type Ca2+ channels, measured in rat brain membranes using [3H]isradipine, indicated a Ki value of 0.694 microM, and the compound is thus nonselective between A3 receptors and L-type Ca2+ channels. Inclusion of a 6-phenyl group enhanced A3 receptor selectivity: Compound 28 (MRS1097; 3,5-diethyl 2-methyl-6-phenyl-4-(trans-2-phenylvinyl)-1,4(R,S)-dihydro-pyridin e-3, 5-dicarboxylate) was 55-fold selective vs A1 receptors, 44-fold selective vs A2A receptors, and over 1000-fold selective vs L-type Ca2+ channels. In addition, compound 28 attenuated the A3 agonist-elicited inhibitory effect on adenylyl cyclase. Furthermore, whereas nicardipine, 12, displaced radioligand from the Na(+)-independent adenosine transporter with an apparent affinity of 5.36 +/- 1.51 microM, compound 28 displaced less than 10% of total binding at a concentration of 100 microM. Pyridine derivatives, when bearing a 4-alkyl but not a 4-phenyl group, maintained affinity for adenosine receptors. These findings indicate that the dihydropyridines may provide leads for the development of novel, selective A3 adenosine antagonists.

Synthesis and Biological Activities of 4-Phenyl-5-pyridyl-1,3-thiazole Derivatives as Selective Adenosine A3 Antagonists

“…27,28) have been reported as new hA 3 AR antagonists. Although these antagonists showed strong hA 3 AR antagonistic activity and good selectivity against other adenosine receptor subtypes, they were found to be weak or ineffective against rat A 3 AR (rA 3 AR), 1,11,12,15,28,29) and could therefore not be evaluated in rat in vivo models. The homology of A 3 AR among several species was reported and the only 72% homology between human and rat A 3 AR was one reason for species differences.…”

“…As human adenosine A 3 receptor (hA 3 AR) antagonists, many potent and selective antagonists, such as xanthine derivatives, 11) 1,4-dihydropyridines, [12][13][14][15] triazoloquinazolines, 16,17) flavonoids, 18) triazolonaphthyridines, 19) thiazolopyrimidines, 19,20) isoquinolines, 21,22) quinazolines, 21) pyrazolotriazolopyrimidines, [23][24][25] thiazoles and thiadiazoles, 26) and triazolopurines 27,28) have been reported as new hA 3 AR antagonists. Although these antagonists showed strong hA 3 AR antagonistic activity and good selectivity against other adenosine receptor subtypes, they were found to be weak or ineffective against rat A 3 AR (rA 3 AR), 1,11,12,15,28,29) and could therefore not be evaluated in rat in vivo models.…”

A New Series of 2-Alkoxy(aralkoxy)-[1,2,4]triazolo[1,5-a]quinazolin-5-ones as Adenosine Receptor Antagonists

“…Moreover, the binding data of theophylline, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and some selective adenosine receptors, included as antagonist reference compounds in Table 2, are also reported. [37][38][39][40][41][42][43][44][45][46][47] Examination of the binding results listed in Table 1 indicated that, the data obtained confirmed the structural modifications carried out on the 5-position of the tricyclic system 1 produces a remarkable modification of the adenosine receptorial profile in terms of affinity and/or selectivity.…”

Recent developments in the field of A3 adenosine receptor antagonists

“…Also, the effect of the stereochemistry at the C 4 center has been evaluated, demonstrating that the S-isomer shows better affinity (about 35-fold) than the R-isomer [Jiang et al, 1999]. The same authors simultaneously evaluated the binding profile of pyridines obtained from the oxidation of the corresponding 1,4-dihydropyridines van Rhee et al, 1996]. These structures showed a general loss of selectivity at hA 3 , except for some derivatives substituted at the 4-position with small alkyl groups.…”