6-phenyl-1,4-dihydropyridine derivatives as potent and selective A(3) adenosine receptor antagonists

An approach to designing dihydropyridines that bind to adenosine receptors without binding to L-type calcium channels has been described. 1,4-Dihydropyridine derivatives substituted with beta-styryl or phenylethynyl groups at the 4-position and aryl groups at the 6-position were synthesized and found to be selective for human A(3) receptors. Combinations of methyl, ethyl, and benzyl esters were included at the 3- and 5-positions. 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-carboxymethyl)phenyl]ethylamino]-5'-(N-ethyl carbamoyl)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-methycarbonyl)adenosine]. Structure-activity analysis indicated that substitution of the phenyl ring of the beta-styryl group but not of the 6-phenyl substituent was tolerated in A(3) receptor selective agents. Replacement of the 6-phenyl ring with a 3-thienyl or 3-furyl group reduced the affinity at A(3) receptors by 4- and g-fold, respectively. A 5-benzyl ester 4-trans-beta-styryl derivative, 26, with a K-i value of 58.3 nM at A(3) receptors, was >1700-fold selective vs either A(1) receptors or A(2A) receptors. Shifting the benzyl ester to the 3-position lowered the affinity at A(3) receptors 3-fold. A 5-benzyl, 3-ethyl ester 4-phenylethynyl derivative, 28, displayed a K-i value of 31.4 nM at A(3) receptors and 1300-fold selectivity vs A(1) receptors. The isomeric 3-benzyl, 5-ethyl diester was >600-fold selective for A(3) receptors. Oxidation of 28 to the corresponding pyridine derivative reduced affinity at A(3) receptors by 88-fold and slightly increased affinity at A(1) receptors.