Medicinal chemistry of the human adenosine A3 receptor

✍ Scribed by Erica W. van Tilburg; Jacqueline E. van Muijlwijk-Koezen; Adriaan P. Ijzerman

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 150 KB
• Volume: 45
• Category: Article
• ISSN: 0272-4391
• DOI: 10.1002/(sici)1098-2299(199811/12)45:3/4<182::aid-ddr15>3.0.co;2-e

✦ Synopsis

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-propylthioadenosine) 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-4yl]-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.