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Medicinal chemistry of the human adenosine A 3 receptor
Author(s) -
van Tilburg Erica W.,
van MuijlwijkKoezen Jacqueline E.,
Ijzerman Adriaan P.
Publication year - 1998
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199811/12)45:3/4<182::aid-ddr15>3.0.co;2-e
Subject(s) - chinese hamster ovary cell , chemistry , adenosine , adenosine receptor , partial agonist , receptor , stereochemistry , adenosine a2b receptor , adenosine a3 receptor , adenosine a1 receptor , intrinsic activity , isoquinoline , agonist , biochemistry
Partial agonists and antagonists were synthesized and evaluated biologically for extended pharmacologic characterization of the human adenosine A 3 receptor. The affinities of all compounds were determined at the human adenosine A 3 receptor stably transfected in HEK 293 cells and in rat brain membranes for the adenosine A 1 and A 2A receptors. The partial agonists were also evaluated for their ability to stimulate [ 35 S]GTPγ[S] binding in Chinese hamster ovary cells expressing the human adenosine A 3 receptor to determine their intrinsic activities. 5′‐(Alkylthio)‐substituted analogs of N 6 ‐(3‐iodobenzyl)adenosine were synthesized in 47–60% overall yields. The compounds proved to be potent and selective partial agonists for the A 3 receptor, displaying affinities in the nanomolar range. N 6 ‐(3‐iodobenzyl)adenosine ( 2 ), 5′‐deoxy‐ N 6 ‐(3‐iodobenzyl)‐5′‐methyl‐thioadenosine ( 4 ), and 5′‐deoxy‐ N 6 ‐(3‐iodobenzyl)‐5′‐ethylthioadenosine ( 5 ) had highest affinities for the A 3 receptor with K i values ranging from 9–28 nM. Compound 6 (5′‐deoxy‐ N 6 ‐(3‐iodobenzyl)‐5′‐ n ‐propyl‐thioadenosine) had the highest (over 200‐fold) A 3 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 A 3 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 A 3 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 A 3 receptor. Furthermore, the effects of mono‐ and disubstitution of the benzamide ring of 9 were investigated. This led to the A 3 ‐selective compound 4‐methoxy‐ N ‐[2‐(2‐pyridinyl)quinazolin‐4‐yl]‐benzamide ( 18 ) with an affinity of 17 nM at the human adenosine A 3 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.