Abstract
A series of N(6)-alkyl-2-alkynyl derivatives of adenosine (Ado) have
been synthesized and evaluated for their affinity at human A(1),
A(2A), and A(3) receptors and for their potency at A(2B) 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 A(1) receptor and slightly
decreased for both A(3) and A(2B) subtypes compared to those of their
corresponding NECA derivatives, whereas the A(2A) receptor affinities
of the two series of nucleosides were similar. The presence of a
methyl group on N(6) of the 2-alkynyladenosines, inducing an increase
in affinity at the human A(3) receptor and a decrease at the other
subtypes, resulted in an increase in A(3) selectivity. In particular,
2-phenylethynyl-N(6)-methylAdo (8b) showed an A(3) affinity in the
low nanomolar range (K(i)(A(3)) = 3.4 nM), with a A(1)/A(3) and A(2A)/A(3)
selectivity of about 500 and 2500, respectively. These findings motivated
us to search for the preparation of new selective radioligands for
the A(3) subtype; hence, a procedure to introduce a tritiated alkylamino
group in these molecules was carried out. As far as the potency at
the A(2B) 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, EC(50)(A(2B))
= 0.22 microM proved to be one of the most potent A(2B) agonist
reported so far. On the other hand, the (S)-2-phenylhydroxypropynyl-N(6)-ethylAdo
(9e, EC(50)(A(2B)) = 0.73 microM) showed a significantly increase
of potency at the A(2B) subtype in comparison with the N(6)-methyl,
N(6)-isopropyl, and the unsubstituted adenosine derivatives, although
it resulted in being less potent than (S)-PHPNECA (1e, EC(50)(A(2B))
= 0.22 microM). These observations suggest that the introduction
of an ethyl group in the N(6)-position and an ethylcarboxamido substituent
in the 4'-position of (S)-2-phenylhydroxypropynyladenosine could
lead to a compound endowed with high potency at the A(2B) receptor.
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