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

R Volpini,S Taffi,S Costanzi,C Lambertucci,S Vittori,K.-N Klotz,F R Portino,G Cristalli,Viktor V Zhdankin

doi:10.3998/ark.5550190.0005.526

Abstract

The synthesis of a new series of 2-(aryl)alkylthio derivatives of N-ethylcarboxamido adenosine (NECA) is described, in comparison with the corresponding derivatives of adenosine. Binding studies (A1, A2A, and A3) and adenylyl cyclase activity (A2B) at human adenosine receptor subtypes stably transfected in Chinese hamster ovary (CHO) cells showed that the 2- (aryl)alkylthioadenosine derivatives are more potent than the corresponding NECA derivatives at A1 receptors, while the NECA derivatives possess highest affinity at both A2A and A3 receptors. Thus, the 2-(1-pentyl)thioadenosine (7) with a Ki A1 = 91 nM, the 2-phenylethylthioNECA (18) with a Ki A2A = 24 nM, and the 2-phenylmethylthioadenosine (11) with a Ki A3 = 68 nM, could be useful tools to be modificated in order to find very potent and selective agonists for the human adenosine receptor subtypes.

Highlights

Adenosine (Ado, 1) is a naturally-occurring nucleoside which is reported to modulate a variety of physiological and pathophysiological processes through the interaction with at least for subtypes of a family of cell-surface G-protein-coupled receptors.1-3 These four adenosine receptors (ARs), named A1, A2A, A2B, and A3, have widespread tissue distribution and are often co-expressed in the same cell type.4The search for potent and selective A2A adenosine receptor agonists has been a target of medicinal chemists, since it is well known that the coronary vasodilation induced by Ado in different species is mediated by activation of A2AAR and a compound capable of producing coronary vasodilation through activation of A2AAR, but that is devoid of A1- and A3-agonist activity would have advantage over Ado for use in myocardial perfusion imaging studies
All the compounds were evaluated at the human recombinant adenosine receptors, stably transfected into Chinese hamster ovary (CHO) cells, utilizing radioligand binding studies (A1, A2A, A3) or adenylyl cyclase activity assay (A2B)
The preference for the different adenosine receptor subtypes seems do not clearly depend on the nature of the substituent present in the two position, in all cases the 2(aryl)alkylthioadenosine derivatives are more potent than the corresponding N-ethylcarboxamido adenosine (NECA) derivatives at A1 receptors,19 while the NECA derivatives possess higher affinity in comparison with adenosines at both A2A and A3 receptors, with the exception of compound 17 which is less active than the corresponding adenosine derivative 11 at A3 receptor subtypes

Summary

Introduction

Adenosine (Ado, 1) is a naturally-occurring nucleoside which is reported to modulate a variety of physiological and pathophysiological processes through the interaction with at least for subtypes of a family of cell-surface G-protein-coupled receptors. These four adenosine receptors (ARs), named A1, A2A, A2B, and A3, have widespread tissue distribution and are often co-expressed in the same cell type.. A series of 2-amino, 2-alkoxy, 2-alkythio-, 2-alkynyl-, and 2-alkenyl-derivatives of adenosine and N-ethylcarboxamidoadenosine (NECA, 2) have been synthesized and tested mainly on different models of rat A1 and A2A receptor subtypes From these studies some ligands, such as CGS 21680 [3], 2-(1-hexyn-1-yl)-5’-N-ethylcarboxamidoadenosine (HENECA, 4), and 2-(3-hydroxy-3-phenyl-1-propyn-1-yl)-5’-N-ethylcarboxamidoadenosine (PHPNECA, 5), showed to possess high A2A affinity combined, in some cases, with good A2A vs A1 selectivity. The effects on affinity at A1 and A2 receptors of concurrent N6 and C5’ modifications, leading to N6-substituted Nalkyladenosine-5’-uronamides, resulted to be less than additive.7 On this basis the synthesis of a new series of 2-(aryl)alkylthio derivatives of NECA was designed to improve the A2A affinity and selectivity of 2-(aryl)alkylthioadenosines which were reported to possess coronary vasodilating activity and platelet aggregation inhibitory activity..

Biological Results and Discussion

PHPNECA

Conclusions

Adenosine Receptors