A unique xanthine derivative KMCP-98 with activation of adenosine receptor subtypes.

摘要

KMCP-98 is a newly synthesized adenosine receptor agonist by alkylation at the 7-position of the xanthines nucleus. We first investigated the pharmacological 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 temporary fall in blood pressure and heart rate, followed by a sustained fall in heart rate in pentobarbital-anesthetized Wistar rats. The hypotensive and bradycardiac responses were inhibited by pretreatment with an A(1) adenosine receptor antagonist 8-phenyltheophylline (8-PT, 0.5 mg/kg). Both KMCP-98 and adenosine (0.3-100 microM) produced negative inotropic activity in isolated guinea pig left atria. The negative inotropic activity of KMCP-98 was significantly blocked by pretreatment with A(1) receptor antagonists 8-PT (10 microM) and xanthine amine congener (XAC, 10 microM), a nonselective adenosine antagonist theophylline (10 microM), a K(+) channel blocker tetraethylammonium (TEA, 10 mM) and a K(ATP) channel blocker glibenclamide (1 microM). KMCP-98 (0.03-30 microM) produced concentration-dependent relaxations in carbachol (1 microM) precontracted guinea pig tracheal smooth muscle. The trachea relaxant response of KMCP-98 was markedly inhibited by A(2), A(2a) and A(2b) adenosine receptor antagonists 3,7-dimethyl-1-propargylxanthine (DMPX, 10 microM), 8-(3-chlorostyryl)caffeine (CSC, 10 microM) and alloxazine (10 microM), respectively, the nitric oxide synthase (NOS) inhibitor L-NAME (100 microM) and also by TEA and glibenclamide. In addition, KMCP-98 (0.03-30 microM) elicited relaxant response in norepinephrine (3 microM) precontracted rat thoracic aorta in a concentration-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, adenosine and 5'-N-ethylcarboxaminoadenosine (NECA) were evaluated in [(3)H]DPCPX and [(3)H]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 cardiac depression, tracheal and aortic smooth muscle relaxations.