In vitro and in vivo pharmacological characterization of N6-cyclopentyl-9-methyladenine (N-0840): a selective, orally active A1 adenosine receptor antagonist.

The pharmacological and biochemical profile of N6-cyclopentyl-9-methyladenine (N-0840) was elucidated in vitro and in vivo. In radioligand binding assays, N-0840 had 14- to 400-fold greater affinity for A1 than A2 adenosine receptors and did not inhibit radioligand binding to alpha-1, alpha-2, beta, 5-hydroxytryptamine 1a, muscarinic, D1 or D2 receptors at concentrations < or = 10,000 nM. In guinea pig tissues, N-0840 competitively antagonized A1 receptor-mediated, 5'-N-ethylcarboxamidoadenosine-induced negative inotropism (paced left atria, KB = 0.83 microM), chronotropism (spontaneously beating right atria, KB = 0.91 microM) and dromotropism (Langendorff heart; KB = 0.72 microM). However, at concentrations up to 100 microM, N-0840 did not antagonize A2 adenosine receptor-mediated, 5'-N-ethylcarboxamidoadenosine-induced relaxations of the guinea pig aorta. N-0840 was a poor inhibitor of total cyclic nucleotide phosphodiesterase activity and of adenosine uptake (IC50 > 200 microM), and it did not inhibit adenosine deaminase activity. In anesthetized rats, N-0840 selectively antagonized A1 adenosine receptor-mediated bradycardia, but generally failed to affect A2 adenosine receptor-mediated vasodilation in the in situ perfused hindquarters (A2/A1 selectivity: > or = 33-fold). The duration of action of N-0840 ranged from 1 min (after 3 mumol/kg i.v.) to 8 hr (after 100 mumol/kg p.o.). N-0840 (< or = 100 mumol/kg i.v.; < or = 1,000 mumol/kg p.o.) had little or no effect on blood pressure or heart rate and produced no adverse drug reactions.(ABSTRACT TRUNCATED AT 250 WORDS)