title: Antilipolytic activity of a novel partial A1 adenosine receptor agonist devoid of cardiovascular effects: comparison with nicotinic acid.
abstract: Elevated lipolysis and circulating free fatty acid (FFA) levels have been linked to the pathogenesis of insulin resistance. A1 adenosine receptor agonists are potent inhibitors of lipolysis. Several A1 agonists have been tested as potential antilipolytic agents; however, their effect on the cardiovascular system remains a potential problem for development of these agents as drugs. In the present study, we report that CVT-3619 [(2-{6-[((1R,2R)-2-hydroxycyclopentyl) amino] purin9-yl} (4S,5 S,2R,3R)5-[(2fluorophenylthio) methyl] oxolane-3,4-diol)], a novel partial A1 receptor agonist, significantly reduces circulating FFA levels without any effect on heart rate and blood pressure in awake rats. Rats were implanted with indwelling arterial and venous cannulas to obtain serial blood samples, record arterial pressure, and administer drug. CVT-3619 decreased FFA levels in a dose-dependent manner at doses from 1 up to 10 mg/kg. The FFA-lowering effect was blocked by the A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine. Triglyceride (TG) levels were also significantly reduced by CVT-3619 treatment in the absence and presence of Triton. Tachyphylaxis of the antilipolytic effect of CVT-3619 (1 mg/kg i.v. bolus) was not observed with three consecutive treatments. An acute reduction of FFA by CVT-3619 was not followed by a rebound increase of FFA as seen with nicotinic acid. The potency of insulin to decrease lipolysis was increased 4-fold (p < 0.01) in the presence of CVT-3619 (0.5 mg/kg). In summary, CVT-3619 is an orally bioavailable A1 agonist that lowers circulating FFA and TG levels by inhibiting lipolysis. CVT-3619 has antilipolytic effects at doses that do not elicit cardiovascular effects.
authors.affiliation: Department of Pharmacology, CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA. arvinder.dhalla@cvt.com
authors.forename: Arvinder K
authors.initials: AK
authors.lastname: Dhalla
authors.forename: Melissa
authors.initials: M
authors.lastname: Santikul
authors.forename: Michelle
authors.initials: M
authors.lastname: Smith
authors.forename: Mei-Yee
authors.initials: MY
authors.lastname: Wong
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D017667:Adipocytes / Q000187:drug effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D009525:Niacin / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood
chemical_list: C510789:2-(6-((2-hydroxycyclopentyl)amino)purin-9-yl)-5-((2-fluorophenylthio)methyl)oxolane-3,4-diol; D058907:Adenosine A1 Receptor Agonists; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D014280:Triglycerides; D009525:Niacin; D011092:Polyethylene Glycols; D000241:Adenosine; C016811:tyloxapol