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

Abstract

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)

• Authors: R J Barrett, J M May, P L Martin, J R Miller
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 265 Issue 1 Pg. 227-36 (Apr 1993) ISSN: 0022-3565 [Print] United States
• PMID: 8386236 (Publication Type: Journal Article)

Chemical References

• Purinergic Antagonists
• Vasodilator Agents
• N(6)-cyclopentyl-9-methyladenine
• 3',5'-Cyclic-AMP Phosphodiesterases
• Adenosine Deaminase
• Adenine
• Adenosine

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (metabolism)
• Adenine (administration & dosage, analogs & derivatives, pharmacology)
• Adenosine (metabolism)
• Adenosine Deaminase (metabolism)
• Administration, Oral
• Animals
• Cattle
• Guinea Pigs
• Heart Rate (drug effects)
• In Vitro Techniques
• Male
• Purinergic Antagonists
• Rabbits
• Radioligand Assay
• Rats
• Vasodilator Agents (pharmacology)