CGS 21680C, an A2 selective adenosine receptor agonist with preferential hypotensive activity.
CGS 21680C (2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethyl-carboxamido adenosine) a 2-substituted analog of the riboside uronamide, 5'-N-ethylcarboxamido adenosine and the related analog CGS 21577 (2-phenethylamino-5'-N-ethylcarboxamido adenosine), have high in vitro affinity for brain striatal adenosine A2 receptors (IC50 values = 22 and 13 nM, respectively). Both compounds were considerably less active at A1 receptors with CGS 21577 and CGS 21680C having respective IC50 values of 0.76 and 3.1 microM. The former compound was thus 59-fold selective for A2 receptors whereas CGS 21680C was 140-fold selective. In contrast, the reference A2 selective ligand, CV 1808 (2-phenylaminoadenosine), showed only 8-fold selectivity as an A2 ligand, having an IC50 of 115 nM in the [3H]-5'N-ethylcarboxamide adenosine assay and an IC50 of 910 nM at the N6-[3H] cyclohexyladenosine site. Further examination of CGS 21680C showed that the compound was without effect on binding to 17 other putative neurotransmitter/neuromodulator sites indicating its selectivity as an adenosine receptor ligand. In an isolated perfused working rat heart model, CGS 21680C effectively increased coronary flow with an ED25 value of 1.8 nM. The corresponding value for CGS 21577 was 3 nM whereas that for CV 1808 was 110 nM. The EC25 for eliciting bradycardia for all three compounds was greater than 1000 nM. The effects of all three compounds could be reversed by treatment with the xanthine adenosine antagonist, xanthine amine congener.(ABSTRACT TRUNCATED AT 250 WORDS)
Hutchison
A J
AJ
Research Department, CIBA-Geigy Corporation, Summit, New Jersey.
Webb
R L
RL
Oei
H H
HH
Ghai
G R
GR
Zimmerman
M B
MB
Williams
M
M
D000241:Adenosine / Q000494:pharmacology / Q000031:analogs & derivatives; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000187:drug effects
D000959:Antihypertensive Agents; D010627:Phenethylamines; D011983:Receptors, Purinergic; C061281:2-phenethylamino-5'-N-ethylcarboxamidoadenosine; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine