Methanocarba ring as a ribose modification in ligands of G protein-coupled purine and pyrimidine receptors: synthetic approaches

Tosh, Dilip K.

doi:10.1039/c2md20348k

Cited by 8 publications

(12 citation statements)

References 47 publications

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“…All of these analogues contain a (N)-methanocarba ring system to optimize A 3 AR affinity, which improves the selectivity in comparison to the ribose series. 5 …”

Section: Discussionmentioning

confidence: 99%

“…1,2 As an extension of the structure activity relationship (SAR) of AR agonists, we have introduced nucleoside derivatives containing in place of ribose a bicyclo[3.1.0]hexane (methanocarba) ring system, which display increased affinity and/or selectivity for the A 3 AR compared to other AR subtypes. 5 The rigid ribose ring substitute maintains a receptor-preferred conformation and thus decreases an entropic energy barrier for receptor binding. Prototypical nucleosides containing a methanocarba ring system in a North (N) envelope conformation are typically >100-fold more potent at the A 3 AR than the corresponding isomers in the South (S) conformation.…”

Section: Introductionmentioning

confidence: 99%

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Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A₃ adenosine receptor agonists

et al. 2015

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2-Arylethynyl derivatives of (N)-methanocarba adenosine 5′-uronamides are selective A3AR (adenosine receptor) agonists. Here we substitute a 1,2,3-triazol-1-yl linker in place of the rigid, linear ethynyl group to eliminate its potential metabolic liability. Docking of nucleosides containing possible short linker moieties at the adenine C2 position using a hybrid molecular model of the A3AR (based on the A2AAR agonist-bound structure) correctly predicted that a triazole would maintain the A3AR selectivity, due to its ability to fit a narrow cleft in the receptor. The analogues with various N6 and C2-aryltriazolyl substitution were synthesized and characterized in binding (Ki at hA3AR 0.3 – 12 nM) and in vivo to demonstrate efficacy in controlling chronic neuropathic pain (chronic constriction injury). Among N6-methyl derivatives, a terminal pyrimidin-2-yl group in 9 (MRS7116) increased duration of action (36% pain protection at 3 h) in vivo. N6-Ethyl 5-chlorothien-2-yl analogue 15 (MRS7126) preserved in vivo efficacy (85% protection at 1 h) with short duration. Larger N6 groups, e.g. 17 (MRS7138, >90% protection at 1 and 3 h), greatly enhanced in vivo activity. Thus, we have combined structure-based methods and phenotypic screening to identify nucleoside derivatives having translational potential.

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“…All of these analogues contain a (N)-methanocarba ring system to optimize A 3 AR affinity, which improves the selectivity in comparison to the ribose series. 5 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A₃ adenosine receptor agonists

et al. 2015

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“…The synthesis of these conformationally locked nucleosides requires long synthetic routes, the various stages of which are described in detail elsewhere [28–32]. Optimization of the synthetic approaches has made this nucleoside class more synthetically tractable and allowed stereochemical purity to be achieved.…”

Section: Conventional Targets Of Nucleosides and Small Nucleotidesmentioning

confidence: 99%

“…At the P2Y 1 R, the (N) conformer was highly favored, whereas at the P2Y 6 R, which is also coupled to G q -protein, the (S) conformer was highly favored [28]. MRS2365 ( 4 ) was enhanced in affinity ( K i = 0.4 nM) as well as selectivity as an agonist of the P2Y 1 R, a platelet receptor that is important in aggregation, in comparison to its ribose analog 2-methylthio-adenosine 5′-diphosphate (2-MeSADP, K i ~ 100 nM).…”

Section: Conventional Targets Of Nucleosides and Small Nucleotidesmentioning

confidence: 99%

Polypharmacology of conformationally locked methanocarba nucleosides

Tosh

Toti

Ciancetta

2017

Drug Discovery Today

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A single molecular scaffold can be adapted to interact with diverse targets, either separately or simultaneously. Nucleosides and nucleotides in which ribose is substituted with bicyclo[3.1.0]hexane are an example of a versatile drug-like scaffold for increasing selectivity at their classical targets: kinases, polymerases, adenosine and P2 receptors. Also, by applying structure-based functional group manipulations, rigidified adenosine derivatives can be repurposed to satisfy pharmacophoric requirements of various GPCRs, ion channels, enzymes and transporters, initially detected as off-target activities. Recent examples include 5HT2B serotonin receptor antagonists and novel dopamine transporter allosteric modulators. This directable target diversity establishes rigid nucleosides as privileged scaffolds.

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“…Prior to the X-ray structural determination, we sought to define the receptor-preferred conformation of the ribose ring chemically by introducing steric constraints on the native, freely-twisting ribose moiety by fusing two small carbocyclic rings. The methanocarba (bicyclo[3.1.0]hexane) ring system (fused cyclopropyl and cyclopentyl rings) freezes opposite twists of a ribose-like moiety (either (N), North or (S), South envelope conformations) when incorporated into nucleoside/nucleotide analogues with the bond of ring fusion at either of two positions [31] . These modifications can enhance or reduce potency at different subtypes of purine receptors in comparison to the ribose moiety [31] .…”

Section: X-ray Structures Of a 2a And P2y mentioning

confidence: 99%

John Daly Lecture: Structure-guided Drug Design for Adenosine and P2Y Receptors

Gao

Paoletta

Kiselev

et al. 2015

Computational and Structural Biotechnology Journal

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We establish structure activity relationships of extracellular nucleosides and nucleotides at G protein-coupled receptors (GPCRs), e.g. adenosine receptors (ARs) and P2Y receptors (P2YRs), respectively. We synthesize selective agents for use as pharmacological probes and potential therapeutic agents (e.g. A3AR agonists for neuropathic pain). Detailed structural information derived from the X-ray crystallographic structures within these families enables the design of novel ligands, guides modification of known agonists and antagonists, and helps predict polypharmacology. Structures were recently reported for the P2Y12 receptor (P2Y12R), an anti-thrombotic target. Comparison of agonist-bound and antagonist-bound P2Y12R indicates unprecedented structural plasticity in the outer portions of the transmembrane (TM) domains and the extracellular loops. Nonphosphate-containing ligands of the P2YRs, such as the selective P2Y14R antagonist PPTN, are desired for bioavailability and increased stability. Also, A2AAR structures are effectively applied to homology modeling of closely related A1AR and A3AR, which are not yet crystallized. Conformational constraint of normally flexible ribose with bicyclic analogues increased the ligand selectivity. Comparison of rigid A3AR agonist congeners allows the exploration of interaction of specific regions of the nucleoside analogues with the target and off-target GPCRs, such as biogenic amine receptors. Molecular modeling predicts plasticity of the A3AR at TM2 to accommodate highly rigidified ligands. Novel fluorescent derivatives of high affinity GPCR ligands are useful tool compounds for characterization of receptors and their oligomeric assemblies. Fluorescent probes are useful for characterization of GPCRs in living cells by flow cytometry and other methods. Thus, 3D knowledge of receptor binding and activation facilitates drug discovery.

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Methanocarba ring as a ribose modification in ligands of G protein-coupled purine and pyrimidine receptors: synthetic approaches

Cited by 8 publications

References 47 publications

Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A₃ adenosine receptor agonists

Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A₃ adenosine receptor agonists

Polypharmacology of conformationally locked methanocarba nucleosides

John Daly Lecture: Structure-guided Drug Design for Adenosine and P2Y Receptors

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Methanocarba ring as a ribose modification in ligands of G protein-coupled purine and pyrimidine receptors: synthetic approaches

Cited by 8 publications

References 47 publications

Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A3 adenosine receptor agonists

Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A3 adenosine receptor agonists

Polypharmacology of conformationally locked methanocarba nucleosides

John Daly Lecture: Structure-guided Drug Design for Adenosine and P2Y Receptors

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Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A₃ adenosine receptor agonists

Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A₃ adenosine receptor agonists