Medicinal chemistry of the human adenosine A3 receptor

Abstract

Partial agonists and antagonists were synthesized and evaluated biologically for extended pharmacologic characterization of the human adenosine A3 receptor. The affinities of all compounds were determined at the human adenosine A3 receptor stably transfected in HEK 293 cells and in rat brain membranes for the adenosine A1 and A2A receptors. The partial agonists were also evaluated for their ability to stimulate [35S]GTPγ[S] binding in Chinese hamster ovary cells expressing the human adenosine A3 receptor to determine their intrinsic activities. 5′‐(Alkylthio)‐substituted analogs of N6‐(3‐iodobenzyl)adenosine were synthesized in 47–60% overall yields. The compounds proved to be potent and selective partial agonists for the A3 receptor, displaying affinities in the nanomolar range. N6‐(3‐iodobenzyl)adenosine (2), 5′‐deoxy‐N6‐(3‐iodobenzyl)‐5′‐methyl‐thioadenosine (4), and 5′‐deoxy‐N6‐(3‐iodobenzyl)‐5′‐ethylthioadenosine (5) had highest affinities for the A3 receptor with Ki values ranging from 9–28 nM. Compound 6 (5′‐deoxy‐N6‐(3‐iodobenzyl)‐5′‐n‐propyl‐thioadenosine) had the highest (over 200‐fold) A3 receptor selectivity. Of all partial agonists, 2 and 4 had the highest intrinsic activities. Subsequently, a series of 3‐(2‐pyridinyl)isoquinoline derivatives was synthesized as potential antagonists for the human adenosine A3 receptor. A structure‐activity relationship was performed at the 1‐position of this series. This analysis indicated that a phenyl group, when coupled by a spacer allowing conjugation on position 1 of the isoquinoline ring, increased the adenosine A3 receptor affinity. Of all spacers tested, a carboxamide proved to be optimal. N‐[2‐(2‐pyridinyl)isoquinolin‐4‐yl]‐benzamide (9) had an affinity of 200 nM at the adenosine A3 receptor. Furthermore, the effects of mono‐ and disubstitution of the benzamide ring of 9 were investigated. This led to the A3‐selective compound 4‐methoxy‐N‐[2‐(2‐pyridinyl)quinazolin‐4‐yl]‐benzamide (18) with an affinity of 17 nM at the human adenosine A3 receptor. These partial agonists and antagonists may be useful tools in the pharmacologic characterization and the investigation of the physiologic function of this receptor. Drug Dev. Res. 45:182–189, 1998. © 1998 Wiley‐Liss, Inc.

1,2,4-Triazolo[4,3-a]quinoxalin-1-one: A Versatile Tool for the Synthesis of Potent and Selective Adenosine Receptor Antagonists

“…Replacement of a hydrogen atom of the 4-amino group of 3 with an acyl moiety ( 20 − 23 ) yielded, in agreement with the literature data, − a strong increment in A 3 potency. Compounds 20 − 23 were all inactive at the A 2A AR.…”