GENERAL PHARMACOLOGY OF SDZ WAG-994, A POTENT SELECTIVE AND ORALLY-ACTIVE ADENOSINE A(1) RECEPTOR AGONIST

The pharmacological properties of 6-cyclohexyl-2'-0-methyladenosine (S DZ WAG 994)-a potent, selective, and orally active adenosine A, recept or agonist-are described. SDZ WAG 994 is a potent (K-D 23 +/- 2 nM, n = 5) and selective (1,090-fold vs. A(2A) receptors) displacer of bindi ng to pig striatal A, receptors and behaves as a full agonist at the A , receptors coupled negatively to adenylate cyclase in rat adipocytes (pEC(50) 6.4 +/- 0.2, n = 3), those which induce contraction of rat sp leen (pEC(50) 7.1 +/- 0.1, n = 13) and those which suppress the respon se to autonomic nerve stimulation in guinea-pig ileum (plC(50) 6.6 +/- 0.1, n = 4) and rat kidney (plC(50) 6.0 +/- 0.1, n = 6). The compound has negligible affinity (pEC(50) < 4, n = 5) for the A(28) receptor w hich mediates relaxation of guinea-pig aorta. In spontaneously hyperte nsive (SH) rats SDZ WAG 994, 0.05-0.5 mg/kg (0.14-1.4 mu mol/kg) po, c aused dose-related and sustained (> 5 h) falls in blood pressure (BP) and heart rate (HR) and suppressed plasma renin activity (PRA); the ca rdiovascular effects could be immediately and fully reversed by an int ravenous injection of 8-(p-sulphophenyl)theophylline, 20 mg/kg (56.4 m u mol/kg). SDZ WAC 994 given via the food at 0.4 and 1.2 mg/kg/day (1. 1 and 3.3 mu mol/kg/day) for 7 or 14 days, respectively, induced dose- related hypotension and bradycardia which were well maintained through out the treatment periods. In the conscious, normotensive dog, SDZ WAG 994, 1 and 3 mg/kg (2.8 and 8.3 mu mol/kg) po, induced substantial, s ustained falls in BP which were accompanied by tachycardia. In salt de pleted squirrel monkeys, SDZ WAG 994, 0.1-0.3 mg/kg (0.2-0.83 mu mol/k g) iv or 0.2-0.6 mg/kg (0.56-1.7 mu mol/kg) po caused dose-related and sustained (> 5 h) bradycardia and suppression of PRA but no change in BP. In rhesus monkeys, SDZ WAC 994, 0.1-1.2 mg/kg (0.28-3.3 mu mol/kg ) po induced sustained bradycardia and suppression of PRA and the plas ma free fatty acid and triglyceride concentrations. The data establish SDZ WAC 994 as a potent, selective, and orally active adenosine A, re ceptor agonist with therapeutic potential in certain cardiovascular an d/or metabolic disease states. (C) 1995 Wiley-Liss, Inc.