Synthesis and biological activity of new potential agonists for the human adenosine A2A receptor.
New adenosine derivatives have been synthesized and tested as putative agonists of adenosine receptors. Compounds 2-6 derive from the introduction of several types of substituents (electron donating, electron withdrawing, and halogens) in the para-position of the phenyl ring of the parent compound 1, and compound 7 lacks the hydroxyl group of amino alcohol 1. In radioligand binding assays using recombinant human A(1), A(2A), A(2B), and A(3) receptors, all compounds showed very low or negligible affinity for A(1) and A(2B) receptors but compounds 3, 5, and 7 displayed a remarkably potent affinity for the A(2A) receptor with K(i) values of 1-5 nM. Bromo derivative 3 displayed a selectivity A(1)/A(2A) = 62 and A(3)/A(2A) = 16 whereas the presence of a hydroxyl group (compound 5) improved the selectivity of A(1)/A(2A) and A(3)/A(2A) to 120- and 28-fold, respectively. When the methoxy derivative 4 lacks the hydroxyl group on the side chain (compound 7), the binding affinity for A(2A) is increased to 1 nM, improving selectivity ratios to 356- and 100-fold against A(1) and A(3), respectively. In Chinese hamster ovary cells transfected with human A(2A) and A(2B) receptors, most compounds showed a remarkable activity for the A(2A) receptor, except chloro derivative 2, with EC(50) values ranging from 1.4 to 8.8 nM. The compounds behaved as good A(2A) agonists, and all were more selective than 5'-(N-ethylcarboxamino)adenosine (NECA), with A(2B)/A(2A) ratios of cAMP accumulation ranging from 48 for compound 2 to 666 for compound 7 while the corresponding A(2B)/A(2A) ratio for NECA was only 9. Compounds 1, 3, 5, and 7 also displayed higher selectivities than NECA up to 100-fold in isolated aortas of rat and guinea pig. In guinea pig tracheal rings precontracted by carbachol, compounds 2 and 4 were more potent than adenosine (100-fold) and NECA (10-fold), whereas compounds 1 and 7 displayed similar effects to NECA. Pretreatment of the tracheal rings with A(2), A(2A), and A(2B) receptor antagonists 3,7-dimethyl-l-propargylxanthine, 8-(3-chlorostyryl)caffeine, and alloxazine produced a marked inhibition of the tracheal relaxations induced by compounds 1, 2, and 4, but none of the compounds showed selectivity toward any of the adenosine receptors.
Bosch
M Pilar
MP
Department of Biological Organic Chemistry, IIQAB (CSIC), 08034 Barcelona, Spain. pbvqob@cid.csic.es
Campos
Francisco
F
Niubó
Itziar
I
Rosell
Gloria
G
Díaz
J Luis
JL
Brea
J
J
Loza
M Isabel
MI
Guerrero
Angel
A
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D058908:Adenosine A2 Receptor Agonists; D043683:Receptors, Adenosine A2; D000242:Cyclic AMP; D000241:Adenosine