Interaction of 1,4-dihydropyridine and pyridine derivatives with adenosine receptors: Selectivity for A(3) receptors

• Published in: Journal of medicinal chemistry Vol. 39; no. 15; pp. 2980 - 2989
• Main Authors: vanRhee, AM, Jiang, JL, Melman, N, Olah, ME, Stiles, GL, Jacobson, KA
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 19.07.1996
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; CENTRAL A-ADENOSINE RECEPTORS; CELLS; INHIBITION; AFFINITY; DIHYDROPYRIDINES; MOLECULAR-CLONING; RAT-BRAIN; ANTAGONISTS; BINDING; CALCIUM-CHANNEL
• ISSN: 0022-2623
• 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 A(1) and A(2A) receptors using [H-3]-(R)-PIA [[H-3]-(R)-N-6-(phenylisopropyl)adenosine] and [H-3]CGS 21680 [[H-3]-2-[[4-(2-carboxyethyl)phenyl]ethylamino]-5'-(N-ethylcarbamoyl)adenosine], respectively. Affinity was determined at cloned human and rat A(3) receptors using [I-125]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 mu M at rat A(1) and A(2A) receptors, respectively, and 3.25 mu M at human A(3) receptors. Similarly, (R)-niguldipine, 14, displayed K-i values of 41.3 and 1.90 mu M at A(1) and A(3) receptors, respectively, and was inactive at A(2A) 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 K-i value of 0.670 mu M at A(3) receptors, was 24-fold selective vs A(1) receptors (K-i = 16.1 mu M) and 74-fold vs A(2A) receptors (K-i = 49.3 mu M). The affinity of 24 at L-type Ca2+ channels, measured in rat brain membranes using [H-3]isradipine, indicated a K-i value of 0.694 mu M, and the compound is thus nonselective between A(3) receptors and L-type Ca2+ channels. Inclusion of a 6-phenyl group enhanced A(3) 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 A(1) receptors, 44-fold selective vs A(2A) receptors, and over 1000-fold selective vs L-type Ca2+ channels. In addition, compound 28 attenuated the A(3) agonist-elicited inhibitory effect on adenylylcyclase. Furthermore, whereas nicardipine, 12, displaced radioligand from the Na+-independent adenosine transporter with an apparent affinity of 5.36 +/- 1.51 mu M, compound 28 displaced less than 10% of total binding at a concentration of 100 mu M. 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 A(3) adenosine antagonists.