Pharmacological characterization of CGS 15943A: a novel nonxanthine adenosine antagonist.
CGS 15943A is a potent adenosine receptor antagonist with a novel nonxanthine heterocyclic ring structure. In vitro, CGS 15943A competitively inhibited the 2-chloroadenosine-induced A2 receptor-mediated relaxation of dog coronary artery strips contracted with KCl (25 mM). Similarly, CGS 15943A blocked 2-chloroadenosine- and N-ethylcarboxamideadenosine-induced A2 receptor-mediated relaxation of histamine-contracted guinea pig tracheal strips. Schild analysis of these results yielded pA2 values of 10.8 and 10.1 for the coronary arteries and the tracheal smooth muscle strips, respectively. In comparison, 8-phenyltheophylline blocked 2-chloroadenosine-induced tracheal response with a pA2 value of 7.0. CGS 15943A was devoid of intrinsic activity, and did not affect either histamine- or KCl-induced contractions of the smooth muscle strips. In the electrically stimulated guinea pig left atrial preparation, CGS 15943A antagonized the A1 receptor-mediated negative inotropic effects of R-phenylisopropyladenosine with a pA2 value of 7.4. In vivo, i.v. administration of CGS 15943A blocked the vasodepressor response to 2-chloradenosine in anesthetized normotensive rats with an ID50 of 0.024 mg/kg. In addition, p.o. administration of CGS 15943A (4.0 mg/kg) to conscious rats inhibited 2-chloroadenosine-induced decreases in diastolic blood pressure; maximal effects were observed 30 min after dosing, with a T1/2 of approximately 103 min. Therefore suggesting that CGS 15943A is an orally active antagonist of adenosine receptors. These results indicate that CGS 15943A antagonized both A1 and A2 receptor-mediated responses with a greater affinity toward the A2 than the A1 receptor subtype.
Ghai
G
G
Research Department, Ciba-Geigy Corporation, Summit, New Jersey.
Francis
J E
JE
Williams
M
M
Dotson
R A
RA
Hopkins
M F
MF
Cote
D T
DT
Goodman
F R
FR
Zimmerman
M B
MB
D015762:2-Chloroadenosine; D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011799:Quinazolines; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000187:drug effects*; D014132:Trachea / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*
D011799:Quinazolines; D011983:Receptors, Purinergic; D014230:Triazoles; D015762:2-Chloroadenosine; D000241:Adenosine; C052410:9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine