8-Bromo-9-alkyl adenine derivatives as tools for developing new adenosine A2A and A2B receptors ligands

Lambertucci, Catia; Antonini, Ippolito; Buccioni, Michela; Ben, Diego Dal; Kachare, Dhuldeo D.; Volpini, Rosaria; Klotz, Karl‐Norbert; Cristalli, Gloria

doi:10.1016/j.bmc.2009.02.030

Cited by 54 publications

(43 citation statements)

References 59 publications

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“…2) 13 . Experimental binding affinities from radioligand binding assays were available for 20 adenine derivatives ( 1 – 17 , 19 , 22 – 23 ) 22, 23 and were determined in this work for three additional adenine-based compounds ( 18 , 20 , and 21 , Supplementary Table 1). The compound pairs differed by one to five heavy atoms and spanned up to >500-fold changes in binding affinity.…”

Section: Resultsmentioning

confidence: 99%

“…Multiple high-resolution crystal structures of the A 2A AR have recently been determined 17, 18 and numerous fragment-sized ligands have been identified to this target 19–21 , making it an ideal test case for evaluating a computational approach. Calculation of relative binding affinities using MD simulations in combination with the free energy perturbation (MD/FEP) method was first benchmarked retrospectively for 23 fragment-sized compounds 22, 23 . The MD/FEP technique was also used to assess multiple binding modes and predict the thermodynamic signatures governing changes in binding affinity, which are both factors of major interest in the optimization process.…”

Section: Introductionmentioning

confidence: 99%

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Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site

Matricon

Ranganathan

Warnick

et al. 2017

Sci Rep

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Fragment-based lead discovery is becoming an increasingly popular strategy for drug discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity leads. As design of leads from fragments is challenging, reliable computational methods to guide optimization would be invaluable. We evaluated using molecular dynamics simulations and the free energy perturbation method (MD/FEP) in fragment optimization for the A2A adenosine receptor, a pharmaceutically relevant G protein-coupled receptor. Optimization of fragments exploring two binding site subpockets was probed by calculating relative binding affinities for 23 adenine derivatives, resulting in strong agreement with experimental data (R2 = 0.78). The predictive power of MD/FEP was significantly better than that of an empirical scoring function. We also demonstrated the potential of the MD/FEP to assess multiple binding modes and to tailor the thermodynamic profile of ligands during optimization. Finally, MD/FEP was applied prospectively to optimize three nonpurine fragments, and predictions for 12 compounds were evaluated experimentally. The direction of the change in binding affinity was correctly predicted in a majority of the cases, and agreement with experiment could be improved with rigorous parameter derivation. The results suggest that MD/FEP will become a powerful tool in structure-driven optimization of fragments to lead candidates.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site

Matricon

Ranganathan

Warnick

et al. 2017

Sci Rep

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“…Cristalli et al reported a series of 2-, 9-and 8-, 9-substituted derivatives with moderate affinities at all the subtypes [29,[56][57][58]. Analyzing their structure activity relationship, it seemed that the presence of a substituent at 2-position decreased the selectivity and the insertion of a bulky groups as a propyl moiety at the 9-position enhanced the affinity and selectivity for the A 2B subtype.…”

Section: Non-xanthinementioning

confidence: 99%

A2B Receptor Ligands: Past, Present and Future Trends

Ortore¹,

Martinelli²

2010

CTMC

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A(2B) adenosine receptors have been investigated in recent years as potential target for the treatment of different pathologies. The involvement of this receptor in processes such as interleukins secretion, Ca(2+) mobilization, hepatic glucose regulation, tumor vascularisation, and cardioprotection have stimulated many researchers to develop specific agonists and antagonists. For many years, the lack of potent and selective A(2B) ligands precluded a deep exploration of their therapeutic prospective; at present, much progress in the field of antagonists led to preclinical studies for different compounds. Less populated is the universe of A(2B) agonists, but really promising for the involvement in ischemic preconditioning. A summary of the most significant advancements in the synthesis of new compounds and of the principal structure activity relationships is reported. The xanthine-based A(2B) antagonists currently show the better profile of affinity and selectivity, as CVT-6883 (CVT-Therapeutics: K(i(A2B))=22 nM, and selectivity higher than 50-fold over other subtypes), MRE-2029-F20 (Baraldi's group: K(i(A2B))=5.5 nM, selectivity >180 fold), LAS38096 (Almirall Prodesfarma: K(i(A2B))=17 nM, selectivity >60 fold), OSIP339391 (OSI Pharmaceuticals: K(i(A2B))=0.5 nM, selectivity >80 fold), PSB601 (Bonn University: K(i(A2B))=3.6 nM, selectivity >140 fold) and the deazaxanthine 32 of Carotti's group (K(i(A2B))=11 nM, selectivity >90 fold). Other recently emerging scaffolds with promising biological profiles are described. With regard to the agonists, many research groups are involved in the discovery of useful agonist radioligands, but the only example of potent and rather selective A(2B) agonists are compound 65, recently synthesized, and BAY-60-6583, that is under preclinical phase investigation.

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“…To obtain the averaged time course of I GABA, single time-course data were normalized to the amplitude value recorded at the first GABA application of the rundown protocol. was obtained by reacting the corresponding 8-bromo analogue ANR168 (29) with ethynylbenzene, using a modification of the classical palladiumcatalyzed cross-coupling reaction (Table S2; Fig. S2) (30).…”

Section: Methodsmentioning

confidence: 99%

Blockage of A _2A and A ₃ adenosine receptors decreases the desensitization of human GABA _A receptors microtransplanted to Xenopus oocytes

Roseti

Palma

Martinello

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We previously found that the endogenous anticonvulsant adenosine, acting through A 2A and A3 adenosine receptors (ARs), alters the stability of currents (I GABA) generated by GABAA receptors expressed in the epileptic human mesial temporal lobe (MTLE). Here we examined whether ARs alter the stability (desensitization) of I GABA expressed in focal cortical dysplasia (FCD) and in periglioma epileptic tissues. The experiments were performed with tissues from 23 patients, using voltage-clamp recordings in Xenopus oocytes microinjected with membranes isolated from human MTLE and FCD tissues or using patch-clamp recordings of pyramidal neurons in epileptic tissue slices. On repetitive activation, the epileptic GABA A receptors revealed instability, manifested by a large I GABA rundown, which in most of the oocytes (Ϸ70%) was obviously impaired by the new A 2A antagonists ANR82, ANR94, and ANR152. In most MTLE tissue-microtransplanted oocytes, a new A 3 receptor antagonist (ANR235) significantly improved IGABA stability. Moreover, patch-clamped pyramidal neurons from human neocortical slices of periglioma epileptic tissues exhibited altered I GABA rundown on ANR94 treatment. Our findings indicate that antagonizing A 2A and A3 receptors increases the IGABA stability in different epileptic tissues and suggest that adenosine derivatives may offer therapeutic opportunities in various forms of human epilepsy.epilepsy ͉ focal cortical dysplasia

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8-Bromo-9-alkyl adenine derivatives as tools for developing new adenosine A2A and A2B receptors ligands

Cited by 54 publications

References 59 publications

Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site

Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site

A2B Receptor Ligands: Past, Present and Future Trends

Blockage of A _2A and A ₃ adenosine receptors decreases the desensitization of human GABA _A receptors microtransplanted to Xenopus oocytes

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8-Bromo-9-alkyl adenine derivatives as tools for developing new adenosine A2A and A2B receptors ligands

Cited by 54 publications

References 59 publications

Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site

Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site

A2B Receptor Ligands: Past, Present and Future Trends

Blockage of A 2A and A 3 adenosine receptors decreases the desensitization of human GABA A receptors microtransplanted to Xenopus oocytes

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Blockage of A _2A and A ₃ adenosine receptors decreases the desensitization of human GABA _A receptors microtransplanted to Xenopus oocytes