2-Chloro-N6-cyclopentyladenosine: a highly selective agonist at A1 adenosine receptors.
2-Chloro-N6-cyclopentyladenosine (CCPA) was synthesized as a potential high affinity ligand for A1 adenosine receptors. Binding of [3H]PIA to A1 receptors of rat brain membranes was inhibited by CCPA with a Ki-value of 0.4 nM, compared to a Ki-value of 0.8 nM for the parent compound N6-cyclopentyladenosine (CPA). Binding of [3H]NECA to A2 receptors of rat striatal membranes was inhibited with a Ki-value of 3900 nM, demonstrating an almost 10,000-fold A1-selectivity of CCPA. CCPA inhibited the activity of rat fat cell membrane adenylate cyclase, a model for the A1 receptor, with an IC50-value of 33 nM, and it stimulated the adenylate cyclase activity of human platelet membranes with an EC50-value of 3500 nM. The more than 100-fold A1-selectivity compares favourably with a 38-fold selectivity of CPA. Thus, CCPA is an agonist at A1 adenosine receptors with a 4-fold higher selectivity and 2-fold higher affinity than CPA, and a considerably higher selectivity than the standard A1 receptor agonist R-N6-phenylisopropyladenosine (R-PIA). CCPA represents the agonist with the highest selectivity for A1 receptors reported so far.
Lohse
M J
MJ
Pharmakologisches Institut, Heidelberg, Federal Republic of Germany.
Klotz
K N
KN
Schwabe
U
U
Cristalli
G
G
Vittori
S
S
Grifantini
M
M
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects / Q000378:metabolism*
D011983:Receptors, Purinergic; C058394:2-chloro-N(6)cyclopentyladenosine; D000262:Adenylyl Cyclases; D000241:Adenosine