NPC 205 is a potent and selective adenosine A₁, receptor antagonist: Correlation among receptor binding, biochemical, and physiological assays

Abstract

: NPC 205 is a potent and selective adenosine A, receptor antagonist: Correlation among receptor binding, biochemical, and physiological assays. Drug Dev. Res. 20:429-443, 1990.The chemical synthesis of 8-aryl-l,3-dialkyl derivatives of xanthine and the ability of these compounds to interact with adenosine A, and A, receptors in vitro (in receptor binding, biochemical, and physiological assays) are described. NPC 205 (1,3-dipropyl-8-[4-hydroxyphenyllxanthine) was the most potent and A,-selective antagonist of the series. NPC 205 was twice as potent at PACPX (1,3-dipropyl-8-[2-amino-4-chlorophenyl] cell membranes. NPC 205 was, in fact, 30-fold more potent and fourfold more selective than PACPX for the AC-coupled A, receptor function and exhibited competitive interactions with A, receptors. In isolated guinea pig atria, NPC 205, NPC 189, NPC 200, arid PACPX all reversed 5"-ethyl-carboxamidoadenosine (NECA)-induced depression of tension and rate. In the Langendorff isolated perfused guinea pig heart preparation, NPC 205 was more potent than PACPX in reversing NECA-mediated depression in developed tension and rate (A,-mediated) and, unlike PACPX, had no effect on coronary perfusion pressure (A,-mediated). Neither NPC 205 or PACPX had significant competitive inhibitory effects on rat heart phosphodiesterase Ill activity in vitro. Together, the results suggest that NPC 205 is a highly potent, selective, and competitive antagonist of adenosine A, receptors and should be useful for examining the physiological significance of A, receptors in vitro and in vivo.

Antagonism of the Cardiodepressant Effects of Adenosine during Acute Hypoxia

“…We used NPC-205, a potent adenosine A 1 antagonist with central and peripheral effects, which is approximately 1,000-fold selective for the A 1 receptor. 19 NPC-205 has no phosphodiesterase activity and is nearly 175-fold more A 1 receptorselective than theophylline. 19 METHODS Study Design.…”

“…19 NPC-205 has no phosphodiesterase activity and is nearly 175-fold more A 1 receptorselective than theophylline. 19 METHODS Study Design. This was a prospective laboratory investigation using a rodent model.…”

Adenosine A1Antagonism Attenuatesβ-adrenergic-resistant Sudden Hypoxic Cardiac Insufficiency

“…*Significantly higher than its vehicle, aminophylline, and dobutamine (C). 10 Because BG-9719 did not increase preinsult cardiac work, such an increase is unlikely to be a class effect of A 1 AdoR selective antagonists. Thus, BG-9719 and possibly other A 1 AdoR selective antagonists have the potential to attenuate cardiac insufficiency that occurs after systemic hypoxia, without producing large increases in preinsult cardiac work.…”

“…14 NPC-205 10 and BG-9719 12 have potent central nervous system activity in vitro. The effects of Ado appear to be partly mediated by the vagus nerve in some species.…”

“…One A 1 AdoR antagonist used was NPC-205, which is approximately 1,000-fold selective for the A 1 AdoR (about 175 times more selective than aminophylline). 10 NPC-205 has a duration of effect of about 60-90 minutes. The other A 1 AdoR antagonist was BG-9719, which is more than 1,800-fold selective for the A 1 AdoR in rats and more than 2,400-fold in humans.…”