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

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 A₁ adenosine receptor antagonist 8-phenyltheophylline (8-PT, 0.5 mg/kg). Both KMCP-98 and adenosine (0.3–100 μM) produced negative inotropic activitity in isolated guinea pig left atria. The negative inotropic activity of KMCP-98 was significantly blocked by pretreatment with A₁ receptor antagonists 8-PT (10 μM) and xanthine amine congener (XAC, 10 μM), a nonselective adenosine antagonist theophylline (10 μM), a K⁺ channel blocker tetraethylammonium (TEA, 10 mM) and a K_ATP channel blocker glibenclamide (1 μM). KMCP-98 (0.03–30 μM) produced concentration-dependent relaxations in carbachol (1 μM) precontracted guinea pig tracheal smooth muscle. The trachea relaxant response of KMCP-98 was markedly inhibited by A₂, A_2a and A_2b adenosine receptor antagonists 3,7-dimethyl-1-propargylxanthine (DMPX, 10 μM), 8-(3-chlorostyryl)caffeine (CSC, 10 μM) and alloxazine (10 μM), respectively, the nitric oxide synthase (NOS) inhibitor l-NAME (100 μM) and also by TEA and glibenclamide. In addition, KMCP-98 (0.03–30 μM) elicited relaxant response in norepinephrine (3 μM) 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 [³H]DPCPX and [³H]CGS 21680 binding to rat cortex and striatum, respectively. The K_i values of KMCP-98 for predominate A₁ and A₂ 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.