2-Alkynyl derivatives of adenosine and adenosine-5'-N-ethyluronamide as selective agonists at A2 adenosine receptors

Abstract

In the search for more selective A2-receptor agonists and on the basis that appropriate substitution at C2 is known to impart selectivity for A2 receptors, 2-alkynyladenosines 2a-d were resynthesized and evaluated in radioligand binding, adenylate cyclase, and platelet aggregation studies. Binding of [3H]NECA to A2 receptors of rat striatal membranes was inhibited by compounds 2a-d with Ki values ranging from 2.8 to 16.4 nM. 2-Alkynyladenosines also exhibited high-affinity binding at solubilized A2 receptors from human platelet membranes. Competition of 2-alkynyladenosines 2a-d for the antagonist radioligand [3H]DPCPX and for the agonist [3H]CCPA gave Ki values in the nanomolar range, and the compounds showed moderate A2 selectivity. In order to improve this selectivity, the corresponding 2-alkynyl derivatives of adenosine-5'-N-ethyluronamide 8a-d were synthesized and tested. As expected, the 5'-N-ethyluronamide derivatives retained the A2 affinity whereas the A1 affinity was attenuated, resulting in an up to 10-fold increase in A2 selectivity. A similar pattern was observed in adenylate cyclase assays and in platelet aggregation studies. A 30- to 45-fold selectivity for platelet A2 receptors compared to A1 receptors was found for compounds 8a-c in adenylate cyclase studies.

Binding of the radioligand [3H]‐SCH 58261, a new non‐xanthine A2A adenosine receptor antagonist, to rat striatal membranes

“…5-Amino-9-chloro-2-(2 -furyl) -1,2,4 -triazolo[1,5 -c]quinazoline (CGS 15943) was kindly supplied by Ciba-Geigy (Summit, NJ, U.S.A.). 2-Hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA) was synthesized by Dr G. Cristalli (Department of Chemical Sciences, University of Camerino, Camerino, Italy) (Cristalli et al, 1992)…”

Adenosine receptor agonists: synthesis and binding affinity of 2- (aryl)alkylthioadenosine derivatives

“…The iodoNECA (14) 14-16 with the appropriate mercaptans in dry DMF at 120 °C using potassium carbonate as a catalyst (Scheme 1 and Table 1). The receptor-stimulated adenylyl cyclase activity expressed as EC 50 , nM.…”

Synthesis of [1,2‐3H]ethylamine hydrochloride and [3H]‐labeled apadenoson for a human ADME study

“…Compound 5 was prepared by a modification of the procedure reported by Cristalli et al 6 Compound 8 was prepared by a modification of the procedure reported by Rieger et al…”