2'-C-Methyl analogues of selective adenosine receptor agonists: synthesis and binding studies.
2'-C-Methyl analogues of selective adenosine receptor agonists such as (R)-PIA, CPA, CCPA, NECA, and IB-MECA were synthesized in order to further investigate the subdomain that binds the ribose moiety. Binding affinities of these new compounds at A1 and A2A receptors in bovine brain membranes and at A3 in rat testis membranes were determined and compared. It was found that the 2'-C-methyl modification resulted in a decrease of the affinity, particularly at A2A and A3 receptors. When such modification was combined with N6-substitutions with groups which induce high potency and selectivity at A1 receptors, the high affinity was retained and the selectivity was increased. Thus, 2-chloro-2'-C-methyl-N6-cyclopentyladenosine (2'-Me-CCPA), which displayed a Ki value of 1.8 nM at A1 receptors, was selective for A1 vs A2A and A3 receptors by 2166- and 2777-fold, respectively, resulting in one of the most potent and A1-selective agonists so far known. In functional assay, this compound inhibited forskolin-stimulated adenylyl cyclase activity with an IC50 value of 13.1 nM, acting as a full agonist.
Franchetti
P
P
Dipartimento di Scienze Chimiche, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Cappellacci
L
L
Marchetti
S
S
Trincavelli
L
L
Martini
C
C
Mazzoni
M R
MR
Lucacchini
A
A
Grifantini
M
M
D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000737:chemistry; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001921:Brain / Q000378:metabolism; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013737:Testis / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D058906:Purinergic P1 Receptor Agonists; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); C058394:2-chloro-N(6)cyclopentyladenosine; C048599:N(6)-cyclopentyladenosine; D000241:Adenosine