CGS-21680C, AN A2 SELECTIVE ADENOSINE RECEPTOR AGONIST WITH PREFERENTIAL HYPOTENSIVE ACTIVITY

Abstract

CGS 21680C (2-[2-carboxyethyl)phenethylamino]-5''-N-ethylcarboxamido adenosine) a 2-substituted analog of the riboside uronamide, 5''-N-ethylcarboxamido adenosine and the related analog CGS 21577 (2-phenethylamino-5''-N-ethylcarboxamido adenosine), have high in vitro affinity for brain striatal adenosine A2 receptors (IC50 values = 22 and 13 nM, respectively). Both compounds were considerably less active at A1 receptors with CGS 21577 and CGS 21680C having respective IC50 values of 0.76 and 3.1 .mu.M. The former compound was thus 59-fold selective for A2 receptors whereas CGS 21680C was 140-fold selective. In contrast, the reference A2 selective ligand, CV 1808 (2-phenylaminoadenosine), showe donly 8-fold selectivity as an A2 ligand, having an IC50 of 115 nM in the [3H]-5''N-ethylcarboxamide adenosine assay and an IC50 of 910 nM at the N6-[3H] cyclohexyladenosine site. Further examination of CGS 21680C showed that the compound was without effect on binding to 17 other putative neurotransmitter/neuromodulator sites indicating its selectivity as an adenosine receptor ligand. In an isolated perfused working rat heart model, CGS 21680C effectively increased coronary flow with an ED25 value of 1.8 nM. The corresponding value for CGS 21577 was 3 nM whereas that for CV 1808 was 110 nM. The EC25 for eliciting bradycardia for all three compounds was > 1000 nM. The effects of all three compounds could be reversed by treatment with the xanthine adenosine antagonist, xanthine amine congener. Given i.v., CGS 21680A, the hydrochloride salt of CGS 21680C, and CGS 21577 reduced blood pressure in an anesthetized normotensive rat model with ED50 values of 9 .mu.g/kg (19 nmol) and 1.8 .mu.g/kg (4.2 nmol). CV 1808 had an ED50 of 28 .mu.g/kg (78 nmol). All three adenosine analogs increased heart rate by up to 15%, the latter effect probably reflecting a reflex tachycardia occurring as a result of the observed decrease in blood pressure. CGS 21680A, CGS 21577 and CV 1808 were active p.o. in the spontaneously hypertensive rat at a dose of 10 mg/kg with efficacy for up to 24 hr. CGS 21680A caused a transient (60 min) increase in heart rate. A similar response was noted with CV 1808. However, CGS 21577 caused a marked increase in heart rate (140 bpm) which was sustained at 70 bpm for up to 24 hr. CGS 21680C, although more potent and selective as an A2 receptor agonist than CV 1808, shows no apparent difference in its ability to lower blood pressure and affect heart rate in the spontaneous hypertensive rat than the latter compound. CGS 21577, because of its profound and prolonged effects on heart rate is unlikely to merit further attention as a potential hypotensive agent.