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

• Published in: Journal of medicinal chemistry 1996-07, Vol.39 (15), p.2980-2989
• Main Authors: van Rhee, A. Michiel, Jiang, Ji-long, Melman, Neli, Olah, Mark E, Stiles, Gary L, Jacobson, Kenneth A
• Format: Article
• Language: English
• Subjects: Adenylyl Cyclase Inhibitors; Animals; Biological and medical sciences; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - metabolism; Calcium Channels - metabolism; Cell Membrane - metabolism; Cerebral Cortex - metabolism; CHO Cells; Cricetinae; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Dihydropyridines - metabolism; Dihydropyridines - pharmacology; Enzyme Inhibitors - pharmacology; Guinea Pigs; Humans; Isradipine - metabolism; Medical sciences; Miscellaneous; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Purinergic P1 Receptor Antagonists; Pyridines - chemical synthesis; Pyridines - metabolism; Rats; Receptors, Purinergic P1 - metabolism; Recombinant Proteins - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9600205

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)-N 6-(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 [N 6-(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 K i values of 19.6 and 63.8 μM at rat A1 and A2A receptors, respectively, and 3.25 μM at human A3 receptors. Similarly, (R)-niguldipine, 14, displayed K i values of 41.3 and 1.90 μM 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-β-styryl derivative, 24, with a K i value of 0.670 μM at A3 receptors, was 24-fold selective vs A1 receptors (K i = 16.1 μM) and 74-fold vs A2A receptors (K i = 49.3 μM). The affinity of 24 at L-type Ca2+ channels, measured in rat brain membranes using [3H]isradipine, indicated a K i value of 0.694 μM, 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-pyridine-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 μM, compound 28 displaced less than 10% of total binding at a concentration of 100 μM. 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.