INVITRO AND INVIVO 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-methyl adenine (N-0840) was elucidated in vitro and in vivo. In radioligand b inding assays, N-0840 had 14- to 400-fold greater affinity for A1 than A2 adenosine receptors and did not inhibit radioligand binding to alp ha-1, alpha-2, beta, 5-hydroxytryptamine1a, muscarinic, D1 or D2 recep tors at concentrations less-than-or-equal-to 10,000 nM. In guinea pig tissues, N-0840 competitively antagonized Al receptor-mediated, 5'-N-e thylcarboxamidoadenosine-induced negative inotropism (paced left atria , K(B) = 0.83 muM), chronotropism (spontaneously beating right atria, K(B) = 0.91 muM) and dromotropism (Langendorff heart; K(B) = 0.72 muM) . However, at concentrations up to 100 muM, N-0840 did not antagonize 2 adenosine receptor-mediated, 5'-N-ethylcarboxamidoadenosine-induced relaxations of the guinea pig aorta. N-0840 was a poor inhibitor of to tal cyclic nucleotide phosphodiesterase activity and of adenosine upta ke (IC50 > 200 muM), and it did not inhibit adenosine deaminase activi ty. In anesthetized rats, N-0840 selectively antagonized A1 adenosine receptor-mediated bradycardia, but generally failed to affect A2 adeno sine receptor-mediated vasodilation in the in situ perfused hindquarte rs (A2/A1 selectivity: greater-than-or-equal-to 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 (less-than-or-equal-to 100, mumol/k g i.v.; less-than-or-equal-to 1,000 Amol/kg p.o.) had little or no eff ect on blood pressure or heart rate and produced no adverse drug react ions. N-0840 is a specific, selective, well-tolerated and orally bioav ailable antagonist at A1 adenosine receptors that has little inhibitor y activity against phosphodiesterase or adenosine uptake and none agai nst adenosine deaminase.