N(6)-alkyl-2-alkynyl derivatives of adenosine as potent and selective agonists at the human adenosine A(3) receptor and a starting point for searching A(2B) ligands.
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.
Volpini
Rosaria
R
Dipartimento di Scienze Chimiche, Università di Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
Costanzi
Stefano
S
Lambertucci
Catia
C
Taffi
Sara
S
Vittori
Sauro
S
Klotz
Karl-Norbert
KN
Cristalli
Gloria
G
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D058906:Purinergic P1 Receptor Agonists; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000480:Alkynes; D008024:Ligands; D058906:Purinergic P1 Receptor Agonists; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D011994:Recombinant Proteins; D000262:Adenylyl Cyclases; D000241:Adenosine