New base-altered adenosine analogues: Synthesis and affinity at adenosine A1 and A2A receptors (original) (raw)
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Biochemical Pharmacology, 2004
The affinity and efficacy at four subtypes (A 1 , A 2A , A 2B and A 3 ) of human adenosine receptors (ARs) of a wide range of 2-substituted adenosine derivatives were evaluated using radioligand binding assays and a cyclic AMP functional assay in intact CHO cells stably expressing these receptors. Similar to previous studies of the N 6 -position, several 2-substituents were found to be critical structural determinants for the A 3 AR activation. The following adenosine 2-ethers were moderately potent partial agonists (K i , nM): benzyl , 3-chlorobenzyl (72), 2-(3chlorophenyl)ethyl (41), and 2-(2-naphthyl)ethyl (130). The following adenosine 2-ethers were A 3 AR antagonists: 2,2-diphenylethyl, 2-(2-norbornan)ethyl, Rand S-2-phenylbutyl, and 2-(2chlorophenyl)ethyl. 2-(S-2-Phenylbutyloxy)a-denosine as an A 3 AR antagonist right-shifted the concentration-response curve for the inhibition by NECA of cyclic AMP accumulation with a K B value of 212 nM, which is similar to its binding affinity (K i = 175 nM). These 2-substituted adenosine derivatives were generally less potent at the A 1 AR in comparison to the A 3 AR, but fully efficacious, with binding K i values over 100 nM. The 2-phenylethyl moiety resulted in higher A 3 AR affinity (K i in nM) when linked to the 2-position of adenosine through an ether group (54), than when linked through an amine (310) or thioether (1960). 2-[2-(l-Naphthyl)ethyloxy]adenosine (K i = 3.8 nM) was found to be the most potent and selective (>50fold) A 2A agonist in this series. Mixed A 2A /A 3 AR agonists have been identified. Interestingly, although most of these compounds were extremely weak at the A 2B AR, 2-[2-(2naphthyl)ethyloxy]adenosine (EC 50 = 1.4 µM) and 2-[2-(2-thienyl)-ethyloxy]adenosine (EC 50 = 1.8 (M) were found to be relatively potent A 2B agonists, although less potent than NECA (EC 50 = 140 nM).
Bioorganic & Medicinal Chemistry Letters, 2001
Some 8-alkynyladenosines were synthesized and evaluated for their adenosine receptor activity, utilizing radioligand binding studies (A 1 , A 2A , A 3 ) or adenylyl cyclase activity assays (A 2B ). Furthermore, the maximal induction of guanosine 5 0 -(gthio)triphosphate ([ 35 S]GTPgS) binding to G proteins and the inhibition of NECA-stimulated binding, in membranes of CHO cells which express the human A 3 receptor, were used to determine the intrinsic activity of these nucleosides at the A 3 adenosine receptor. The results showed that these new adenosine derivatives are very selective ligands for the A 3 receptor subtype and behave as adenosine antagonists, since they do not stimulate basal [ 35 S]GTPgS binding, but inhibit NECA-stimulated binding. This is the first report that adenosine derivatives, with unmodified ribose moiety, are adenosine receptor antagonists. #
New strategies for the synthesis of A3 adenosine receptor antagonists
Bioorganic & Medicinal Chemistry, 2003
New A 3 adenosine receptor antagonists were synthesized and tested at human adenosine receptor subtypes. An advanced synthetic strategy permitted us to obtain a large amount of the key intermediate 5 that was then submitted to alkylation procedures in order to obtain the derivatives 6-8. These compounds were then functionalised into ureas at the 5-position (compounds 9-11, 18 and 19) to evaluate their affinity and selectivity versus hA 3 adenosine receptor subtype; in particular, compounds 18 and 19 displayed a value of affinity of 4.9 and 1.3 nM, respectively. Starting from 5, the synthetic methodologies employed permitted us to perform a rapid and a convenient divergent synthesis. A further improvement allowed the regioselective preparation of the N 8substituted compound 7. This method could be used as an helpful general procedure for the design of novel A 3 adenosine receptor antagonists without the difficulty of separating the N 8 -substituted pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines from the corresponding N 7 -isomers. #
Synthesis of hypermodified adenosine derivatives as selective adenosine A3 receptor ligands
2006
We investigated the A 3 AR affinity and selectivity of a series of 2-substituted 3 0 -azido and 3 0 -amino adenosine derivatives as well as some 5 0 -uronamide derivatives thereof. All compounds showed high A 3 AR selectivity. While the 3 0 -azides appeared to be A 3 AR antagonists with moderate A 3 AR affinity, their 3 0 -amino congeners exhibit significantly improved A 3 AR affinity and behave as partial agonists. For both the 3 0 -azides and the 3 0 -amines, the 5 0 -methylcarbamoyl modification improved the overall affinity. Introduction of a 2-phenylethynyl substituent provided high affinity for the A 3 AR.
Journal of medicinal …, 2009
To further investigate new potent and selective human A 1 adenosine receptor agonists, we have synthesized a series of 5′-chloro-5′-deoxy-and 5′-(2-fluorophenylthio)-5′-deoxy-N 6 -cycloalkyl(bicycloalkyl)-substituted adenosine and 2′-C-methyladenosine derivatives. These compounds were evaluated for affinity and efficacy at human A 1 , A 2A , A 2B , and A 3 adenosine receptors. In the series of N 6 -cyclopentyl-and N 6 -(endo-norborn-2-yl)adenosine derivatives, 5′-chloro-5′-deoxy-CPA (1) and 5′-chloro-5′-deoxy-(()-ENBA (3) displayed the highest affinity in the subnanomolar range and relevant selectivity for hA 1 vs the other human receptor subtypes. The higher affinity and selectivity of 5′-chloro-5′-deoxyribonucleoside derivatives 1 and 3 for hA 1 AR vs hA 3 AR compared to that of the parent 5′-hydroxy compounds CPA and (()-ENBA was rationalized by a molecular modeling analysis. 5′-Chloro-5′-deoxy-(()-ENBA, evaluated for analgesic activity in the formalin test in mice, was found to inhibit the first or the second phases of the nocifensive response induced by intrapaw injection of formalin at doses ranging between 1 and 2 mg/kg i.p. D-ribofuranosyl)purine (15), prepared as reported by Hou et al., 7 with (()-endo-norborn-2-yl-amine hydrochloride in the presence of triethylamine in absolute ethanol, followed by sugar deblocking with methanolic ammonia, gave 2-Cl-(()-ENBA (16). Compound 16 was protected as 2′,3′-isopropylidene derivative 17 using camphorsulfonic acid and 2,2-dimethoxypropane in acetone in 80% yield. Conversion of 17 to 5′-chloro derivative 18 was performed by treatment with a mixture of thionyl chloride, pyridine, and acetonitrile. Finally, deprotection of 18 with 70% formic acid at 40°C furnished compound 4. Direct conversion of 2-Cl-(()-ENBA (16) into its 5′-chloro-5′-deoxy derivative 4 using thionyl chloride and pyridine in acetonitrile or thionyl chloride and hexamethylphosphoramide (HMPA) was also tried, but low yields of 4 were obtained.
Recent developments in the field of A3 adenosine receptor antagonists
Drug Development Research, 2003
Adenosine is an endogenous modulator of a large variety of physiological functions through the interaction with specific cell membrane G-protein-coupled receptors classified as A 1 , A 2A , A 2B , and A 3 . Activation of A 3 receptors has been shown to stimulate phospholipase C and to inhibit adenylate cyclase. A 3 agonists also cause stimulation of phospholipase D and the release of inflammatory mediators, such as histamine from mast cells, which are responsible for inflammation and hypotension. For these reasons, the clinical use of A 3 adenosine receptors antagonists for the treatment of asthma and inflammatory disease has been suggested. Recent studies also indicated a possible employment of these derivatives as antitumor agents. Different classes of polyheterocyclic compounds have been identified as potent A 3 antagonists. Herein, we report our past and recent results in the development of tricyclic A 3 selective antagonists. The pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine nucleus has especially been investigated by our group. Our interests were focused on the effects of substitution of the phenyl ring of the arylcarbamoyl moiety at N 5 position and of substituents at C 9 and/or at N 8 pyrazole nitrogen. These studies allowed us to obtain a large variety of compounds which showed affinities in the nanomolar range with human A 3 adenosine receptors with a high degree of selectivity vs. all other receptors subtypes. Thanks to the introduction of alkylating groups at p-position of the N 5 -phenylcarbamoyl chain, we succeeded in realizing potent irreversible A 3 adenosine antagonists. Finally, the replacement of the phenyl nucleus of carbamoyl function with a pyridine ring conferred water solubility to the corresponding derivatives, which are also characterized by high levels of A 3 affinity and selectivity. Drug Dev. Res.
Journal of Medicinal Chemistry, 2007
2, N 6 , and/or 5′ substituted adenosine derivatives were synthesized via alkylation of 2-oxypurine nucleosides leading to 2-aralkylether derivatives. 2-(3-(Indolyl)ethyloxy)adenosine 17 was found to be a potent agonist of the human A 2B AR in both binding and cAMP assays. Simplification, altered connectivity and mimicking of the indole ring of 17 failed to maintain A 2B AR potency. Introduction of N 6 -ethyl or N 6 -guanidino substitution, shown to favor A 2B AR potency, failed to enhance potency in the 2-(3-(indolyl)ethyloxy)adenosine series. Indole 5″-or 6″-halo substitution was favored at the A 2B AR, but a 5′-N-ethylcarboxyamide did not further enhance potency. 2-(3″-(6″-Bromoindolyl)ethyloxy)adenosine 28 displayed an A 2B AR EC 50 value (nM) of 128, i.e. more potent than the parent 17 (299) and similar to 5′-N-ethylcarboxamidoadenosine (140). 28 was a full agonist at A 2B and A 2A ARs and a low efficacy partial agonist at A 1 and A 3 ARs. Thus, we have identified and optimized 2-(2-arylethyl)oxo moieties in AR agonists that enhance A 2B AR potency and selectivity.
Bioorganic & Medicinal Chemistry, 2009
Truncated N 6 -substituted-4′-oxo-and 4′-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A 2A and A 3 adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladiumcatalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA 2A AR, but hydrophobic C8 substitution abolished binding at the hA 2A AR. However, most of synthesized compounds displayed medium to high binding affinity at the hA 3 AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA 2A AR agonists. C2 substitution probed geometrically through hA 2A AR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA 2A AR agonist and hA 3 AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.
Synthesis and Biological Activity of New Potential Agonists for the Human Adenosine A 2A Receptor
Journal of Medicinal Chemistry, 2004
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.
Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering
Handbook of Experimental Pharmacology, 2009
A 3 adenosine receptor (A 3 AR) ligands have been modified to optimize their interaction with the A 3 AR. Most of these modifications have been made to the N 6 and C2 positions of adenine as well as the ribose moiety, and using a combination of these substitutions leads to the most efficacious, selective, and potent ligands. A 3 AR agonists such as IB-MECA and Cl-IB-MECA are now advancing into Phase II clinical trials for treatments targeting diseases such as cancer, arthritis, and psoriasis. Also, a wide number of compounds exerting high potency and selectivity in antagonizing the human (h)A 3 AR have been discovered. These molecules are generally characterized by a notable structural diversity, taking into account that aromatic nitrogencontaining monocyclic (thiazoles and thiadiazoles), bicyclic (isoquinoline, quinozalines, (aza)adenines), tricyclic systems (pyrazoloquinolines, triazoloquinoxalines, pyrazolotriazolopyrimidines, triazolopurines, tricyclic xanthines) and nucleoside derivatives have been identified as potent and selective A 3 AR antagonists. Probably due to the "enigmatic" physiological role of A 3 AR, whose activation may produce opposite effects (for example, concerning tissue protection in inflammatory and cancer cells) and may produce effects that are species dependent, only a few molecules have reached preclinical investigation. Indeed, the most advanced A 3 AR antagonists remain in preclinical testing. Among the antagonists described above, compound OT-7999 is expected to enter clinical trials for the treatment of glaucoma, while several thiazole derivatives are in development as antiallergic, antiasthmatic and/or antiinflammatory drugs.