The utilization of a unified pharmacophore query in the discovery of new antagonists of the adenosine receptor family

Webb, Thomas R.; Melman, Neli; Lvovskiy, Dmitriy; Ji, Xingchen; Jacobson, Kenneth A.

doi:10.1016/s0960-894x(99)00583-1

Cited by 29 publications

(21 citation statements)

References 19 publications

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“…Methods utilized in these recent investigations include: conformationally constraining the ribose, or ribose-like, moiety of nucleosides and nucleotides to freeze a conformation that may provide favorable affinity and/or selectivity at P1 and P2 receptors [3,4]; modifying known receptor antagonists [5][6][7]; use of a template approach based on the pyridine family for the design of novel adenosine antagonists [8]; and the screening of chemical libraries in conjunction with molecular modeling [9].…”

Section: Introductionmentioning

confidence: 99%

Structurally related nucleotides as selective agonists and antagonists at P2Y1 receptors

et al. 2001

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The P2Y 1 receptor responds to adenine nucleotides and is present in platelets, heart, smooth muscles prostate, ovary, and brain. A selective antagonist may be useful as an antithrombotic agent. We have analyzed the binding site of this G protein-coupled receptor using ligand design, site-directed mutagenesis, and homology modeling based on rhodopsin. We have designed and synthesized a series of deoxyadenosine 3′,5′-bisphosphate derivatives that act as antagonists, or, in some cases with small structural changes, as agonists or partial agonists. The 2-position accommodates Cl or thioethers, whereas the N 6 -position is limited to Me or Et. 2′-Substitution with OH or OMe increases agonist efficacy over 2′-H. Using molecular modeling of the binding site, the oxygen atoms of the ribose moiety were predicted to be non-essential, i.e. no specific Hbonds with the receptor protein appear in the model. We have, therefore, substituted this moiety with carbocylics, smaller and larger rings, conformationally constrained rings, and acyclics, with retention of affinity for the receptor. With simplified pharmacophores we are exploring the steric and electronic requirements of the receptor binding site, and the structural basis of receptor activation.

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Section: Introductionmentioning

confidence: 99%

Structurally related nucleotides as selective agonists and antagonists at P2Y1 receptors

et al. 2001

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“…To further understand the structure-activity relationships of the most potent A 2B antagonist discovered (38, CMB 6446) in our previously reported pharmacophore searching efforts, 3 and to explore structural modifications that might lead to enhanced selectivity we set about the iterative collection, synthesis and assay of structurally related compounds. In order to facilitate this process we used 2-guanidinylquinazoline substructure searches in ISISBase to search a large available database of compounds (~100,000 from Express-Pick™, available from ChemBridge corporation) the same database that was originally used for the pharmacophore based queries (CNS-Set™).…”

Section: Resultsmentioning

confidence: 99%

“…Further, we also wished to explore the utility of pharmacophore database queries for the discovery of new leads. 3 An unexpected added benefit of our approach was the discovery of new selective leads for related AR subtypes, A 1 , A 2A , and A 2B . This ability to find new structural series from pharmacophore information for an existing bioactive structural series is advantageous in the development of new drug leads.…”

Section: Discussionmentioning

confidence: 99%

“…3 During this study we discovered one compound that showed significant binding to all AR subtypes at 10 micromolar concentration (38, CMB 6446), but also showed some selectivity for the A 2B AR. In order to determine whether this compound that bound to the A 2B AR was already optimized for potency among the members of this chemical series present in the database originally searched, we conducted substructure-based searching and AR assays on other substructure 'hits'.…”

Section: Introductionmentioning

confidence: 95%

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Quinazolines as adenosine receptor antagonists: SAR and selectivity for A2B receptors

Webb

Lvovskiy

Kim

et al. 2003

Bioorganic & Medicinal Chemistry

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We have recently reported the discovery of numerous new compounds that are selective inhibitors of all of the subtypes of the adenosine receptor family via a pharmacophore database searching and screening strategy. During the course of this work we made the unexpected discovery of a potent A 2B receptor antagonist, 4-methyl-7-methoxyquinazolyl-2-(2′-amino-4′-imidazolinone) (38, CMB 6446), which showed selectivity for this receptor and functioned as an antagonist, with a binding K i value of 112 nM. We explored the effects of both substituent-and ring-structural variations on the receptor affinity in this series of derivatives, which were found to be mostly nonselective adenosine receptor ligands with K i values in the micromolar range. Since no enhancement of A 2B receptor affinity of 38 was achieved, the previously reported pharmacophorebased searching strategy yielded the most potent and selective structurally-related hit in the database originally searched.

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“…pyridine family for the design of novel adenosine antagonists (8); and the screening of chemical libraries in conjunction with molecular modeling (9).…”

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confidence: 99%

Ribose Modified Nucleosides and Nucleotides as Ligands for Purine Receptors

Ravi

Nandanan

Kim

et al. 2001

Nucleosides, Nucleotides and Nucleic Acids

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Molecular modeling of receptors for adenosine and nucleotide (P2) receptors with docked ligand, based on mutagenesis, was carried out. Adenosine 3 ′ ,5 ′ -bisphosphate derivatives act as selective P2Y 1 antagonists/partial agonists. The ribose moiety was replaced with carbocyclics, smaller and larger rings, conformationally constrained rings, and acyclics, producing compounds that retained receptor affinity. Conformational constraints were built into the ribose rings of nucleoside and nucleotide ligands using the methanocarba approach, i.e. fused cyclopropane and cyclopentane rings in place of ribose, suggesting a preference for the Northern (N) conformation among ligands for P2Y 1 and A 1 and A 3 ARs.Modulation of adenosine receptors (P1) and nucleotide (P2) receptors by selective agonists and antagonists (1,2) has the potential for the treatment of wide range of diseases, including those of the cardiovascular, inflammatory, and central nervous systems. There are four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ), all of which are G protein-coupled receptors (GPCRs) generally coupled to adenylate cyclase. Extracellular nucleotides, principally ATP, ADP, UTP, and UDP, act through two families of membrane-bound P2 receptors: P2Y subtypes, GPCRs which are activated by both adenine and uracil nucleotides and generally coupled to phospholipase C; and P2X subtypes, ligand-gated ion channels which are activated principally by adenine nucleotides (2). As many as seven subtypes have been cloned within each family. Agonists of adenosine and P2 receptors are almost exclusively nucleosides and nucleotides, respectively, while antagonists of these receptors are structurally more diverse (1). In comparison to the adenosine receptors, much less is known about the specific effects of P2 receptors, largely due to the lack of selective ligands.We are currently designing and synthesizing novel ligands for both adenosine and P2 receptors. Recent methods utilized in these investigations include: conformationally constraining the ribose, or ribose-like, moiety of nucleosides and nucleotides to freeze a conformation that may provide favorable affinity and/or selectivity at P1 and P2 receptors (3,4); modifying known receptor antagonists (5-7); use of a template approach based on the

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The utilization of a unified pharmacophore query in the discovery of new antagonists of the adenosine receptor family

Cited by 29 publications

References 19 publications

Structurally related nucleotides as selective agonists and antagonists at P2Y1 receptors

Structurally related nucleotides as selective agonists and antagonists at P2Y1 receptors

Quinazolines as adenosine receptor antagonists: SAR and selectivity for A2B receptors

Ribose Modified Nucleosides and Nucleotides as Ligands for Purine Receptors

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