6-phenyl-1,4-dihydropyridine derivatives as potent and selective A3 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 A3 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 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-ethylcarbamoyl)-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 A3 receptor selective agents. Replacement of the 6-phenyl ring with a 3-thienyl or 3-furyl group reduced the affinity at A3 receptors by 4- and 9-fold, respectively. A 5-benzyl ester 4-trans-beta-styryl derivative, 26, with a Ki value of 58.3 nM at A3 receptors, was > 1700-fold selective vs either A1 receptors or A2A receptors. Shifting the benzyl ester to the 3-position lowered the affinity at A3 receptors 3-fold. A 5-benzyl, 3-ethyl ester 4-phenylethynyl derivative, 28, displayed a Ki value of 31.4 nM at A3 receptors and 1300-fold selectivity vs A1 receptors. The isomeric 3-benzyl, 5-ethyl diester was > 600-fold selective for A3 receptors. Oxidation of 28 to the corresponding pyridine derivative reduced affinity at A3 receptors by 88-fold and slightly increased affinity at A1 receptors.
Jiang
J L
JL
Molecular Recognition Section, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, USA.
van Rhee
A M
AM
Melman
N
N
Ji
X D
XD
Jacobson
K A
KA
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D004095:Dihydropyridines; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D011994:Recombinant Proteins