A unique xanthine derivative KMCP-98 with activation of adenosine receptorsubtypes

KMCP-98 is a newly synthesized adenosine receptor agonist by alkylation at the 7-position of the xanthines nucleus. We first investigated the pharmaco logical activities of KMCP-98 under in vivo and in vitro conditions. Acute intravenous injection of KMCP-98 (1.0, 2.0 and 3.0 mg/kg) produced a tempor ary fall in blood pressure and heart rate, followed by a sustained fall in heart rate in pentobarbital-anesthetized Wistar rats. The hypotensive and b radycardiac responses were inhibited by pretreatment with an A(1) adenosine receptor antagonist 8-phenyltheophylline (8-PT, 0.5 mg/kg). Both KMCP-98 a nd adenosine (0.3 - 100 muM) produced negative inotropic activitity in isol ated guinea pig left atria. The negative inotropic activity of KMCP-98 was significantly blocked by pretreatment with A(1) receptor antagonists 8-PT ( 10 muM) and xanthine amine congener (XAC, 10 muM), a nonselective adenosine antagonist theophylline (10 muM), a K channel blocker tetraethylammonium ( TEA, 10 mm) and a K-ATP channel blocker glibenclamide (1 muM). KMCP-98 (0.0 3 - 30 muM) produced concentration-dependent relaxations in carbachol (1 mu m) precontracted guinea pig tracheal smooth muscle. The trachea relaxant re sponse of KMCP-98 was markedly inhibited by A(2), A(2a) and A(2b) adenosine receptor antagonists 3,7-dimethyl-1-propargylxanthine (DMPX, 10 muM), 8-(3 -chlorostyryl)caffeine (CSC, 10 M) and alloxazine (10 [M), respectively, th e nitric oxide synthase (NOS) inhibitor L-NAME (100 muM) and also by TEA an d glibenclamide. In addition, KMCP-98 (0.03 - 30 muM) elicited relaxant res ponse in norepinephrine (3 muM) precontracted rat thoracic aorta in a conce ntration-dependent manner. The thoracic aorta relaxant response of KMCP-98 was also significantly inhibited by DMPX, CSC, alloxazine, L-NAME, TEA and glibenclamide. Furthermore, the binding characteristics of KMCP-98, adenosi ne and 5 ' -N-ethylcarboxaminoadenosine (NECA) were evaluated in [H-3]DPCPX and [H-3]CGS 21680 binding to rat cortex and striatum, respectively. The K -i values of KMCP-98 for predominate A(1) and A(2) adenosine receptor sites were 3908 +/- 952 and 158 +/- 10 nM, respectively. In conclusion, KMCP-98 was found to be a xanthine-based adenosine receptor agonist associated card iac depression, tracheal and aortic smooth muscle relaxations. (C) 2001 Els evier Science Inc. All rights reserved.