N6-Alkyl-2-alkynyl Derivatives of Adenosine as Potent and Selective Agonists at the Human Adenosine A3Receptor and a Starting Point for Searching A2BLigands
- 18 June 2002
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 45 (15) , 3271-3279
- https://doi.org/10.1021/jm0109762
Abstract
A series of N6-alkyl-2-alkynyl derivatives of adenosine (Ado) have been synthesized and evaluated for their affinity at human A1, A2A, and A3 receptors and for their potency at A2B adenosine receptor subtypes. The corresponding 2-(1-alkynyl) derivatives of 5‘-N-ethylcarboxamidoadenosine (NECA) and Ado are used as reference compounds. Binding studies demonstrated that the activities of 2-alkynylAdos were slightly increased for the adenosine A1 receptor and slightly decreased for both A3 and A2B subtypes compared to those of their corresponding NECA derivatives, whereas the A2A receptor affinities of the two series of nucleosides were similar. The presence of a methyl group on N6 of the 2-alkynyladenosines, inducing an increase in affinity at the human A3 receptor and a decrease at the other subtypes, resulted in an increase in A3 selectivity. In particular, 2-phenylethynyl-N6-methylAdo (8b) showed an A3 affinity in the low nanomolar range (Ki(A3) = 3.4 nM), with a A1/A3 and A2A/A3 selectivity of about 500 and 2500, respectively. These findings motivated us to search for the preparation of new selective radioligands for the A3 subtype; hence, a procedure to introduce a tritiated alkylamino group in these molecules was carried out. As far as the potency at the A2B receptor, the type of 2-alkynyl chain and the presence of the ethylcarboxamido group on the sugar seem to be very important; in fact, the (S)-2-phenylhydroxypropynylNECA [(S)-PHPNECA, 1e, EC50(A2B) = 0.22 μM] proved to be one of the most potent A2B agonist reported so far. On the other hand, the (S)-2-phenylhydroxypropynyl-N6-ethylAdo (9e, EC50(A2B) = 0.73 μM) showed a significantly increase of potency at the A2B subtype in comparison with the N6-methyl, N6-isopropyl, and the unsubstituted adenosine derivatives, although it resulted in being less potent than (S)-PHPNECA (1e, EC50(A2B) = 0.22 μM). These observations suggest that the introduction of an ethyl group in the N6-position and an ethylcarboxamido substituent in the 4‘-position of (S)-2-phenylhydroxypropynyladenosine could lead to a compound endowed with high potency at the A2B receptor.Keywords
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