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Characterization of potent ligands at human recombinant adenosine receptors

✍ Scribed by Gloria Cristalli; Emidio Camaioni; Stefano Costanzi; Sauro Vittori; Rosaria Volpini; Karl-Norbert Klotz

Publisher: John Wiley and Sons
Year: 1998
Tongue: English
Weight: 120 KB
Volume: 45
Category: Article
ISSN: 0272-4391
DOI: 10.1002/(sici)1098-2299(199811/12)45:3/4<176::aid-ddr14>3.0.co;2-g

No coin nor oath required. For personal study only.

✦ Synopsis

The four adenosine receptor subtypes have been stably transfected into Chinese hamster ovary (CHO) cells allowing for comparative studies in a similar cellular background, using radioligand binding studies (A 1 , A 2A , A 3 ) or adenylyl cyclase activity assays (A 2B ). We are currently using the transfected CHO cells for extensive screening of nucleosides and purine derivatives of our library. Screening of a number of 2-alkynyl analogs of 5´-N-ethylcarboxamidoadenosine (NECA) indicated that introduction of particular substituents, such as the racemic 2-phenylhydroxypropynyl group, led to a highly potent, nonselective agonist at A 1 , A 2A , and A 3 subtypes (PHPNECA, K i in the low nanomolar range at the three subtypes). In the A 2B functional assay, it has been found that PHPNECA (EC 50 A 2B = 0.88 mM) is threefold more potent than NECA. This article is the first report in which the introduction of a bulky group in the 2-position of NECA led to a compound that is active as an agonist at the human A 2B subtype. On the other hand, the presence of a phenyl ring conjugated to the triple bond as in phenylethynylNECA (PENECA) enhanced selectivity for the A 3 subtype. In the purine series (potential antagonists), 8-bromo-9-ethyladenine (8-BEA) showed good affinity toward all adenosine receptor subtypes (K i A 1 = 0.28 mM, K i A 2A = 0.052 mM, K i A 2B = 0.84 mM, K i A 3 = 27.8 mM). On the other hand, the introduction of alkynyl chains in the 8-position resulted in an increased affinity at the A 3 receptor (8-hexynyl-9-ethyladenine, 8-HEEA, K i A 3 = 0.62 mM and 8-phenylethynyl-9-ethyladenine, 8-PEEA, K i A 3 = 0.086 mM).

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