Acyclic Analogues of Deoxyadenosine 3‘,5‘-Bisphosphates as P2Y<sub>1</sub> Receptor Antagonists

Yc, Kim; Gallo‐Rodriguez, Carola; Sy, Jang; Nandanan, E.; Adams, Mary; Tk, Harden; Jl, Boyer; Jacobson, Kenneth A.

doi:10.1021/jm9905211

Cited by 30 publications

(53 citation statements)

References 27 publications

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“…The involved receptor (P2Y 1 receptor), G protein (Ga11), and phospholipase C (PLC-bt) all were identi®ed, puri®ed, and cloned (Boyer et al, 1996b). This model system has been highly useful for identi®cation of P2Y 1 receptor agonists (Boyer et al, , 1996c and antagonists Camaioni et al, 1998;Kim et al, 2000). Our preliminary studies suggested high anity of MRS2279 for the P2Y 1 receptor of turkey erythrocytes .…”

Section: Resultsmentioning

confidence: 88%

“…This receptor is relatively broadly distributed in the central nervous system and in peripheral tissues (Ralevic & Burnstock, 1998;Webb & Barnard, 1999), and its role in the platelet aggregation response to ADP has been a topic of increased interest (Leon et al, 1997(Leon et al, , 1999Jin et al, 1998;Hechler et al, 1998;Fabre et al, 1999). Our initial observation that adenosine bisphosphate molecules are competitive antagonists of the P2Y 1 receptor (Boyer et al, 1996a) has been followed by directed chemical syntheses of new molecules exhibiting potential as selective competitive antagonists of the P2Y 1 receptor Kim et al, 2000). We recently reported the synthesis of a series of ribosemodi®ed-2'-deoxyadenosine bisphosphate analogs .…”

Section: Introductionmentioning

confidence: 99%

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2‐Chloro N⁶‐methyl‐(N)‐methanocarba‐2′‐deoxyadenosine‐3′,5′‐bisphosphate is a selective high affinity P2Y₁ receptor antagonist

Boyer

Adams

Ravi

et al. 2002

British J Pharmacology

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1 We reported previously that bisphosphate derivatives of adenosine are antagonists of the P2Y 1 receptor and that modi®cation of the ribose in these analogues is tolerated in the P2Y 1 receptor binding pharmacophore. 2 Here we delineate the pharmacological activity of one such non-nucleotide molecule, 2-chloro N 6 -methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate (MRS2279), in which the ribose is replaced by a cyclopentane ring constrained in the (N)-conformation by a cyclopropane moiety. 3 MRS2279 antagonized 2MeSADP-stimulated inositol phosphate formation in turkey erythrocyte membranes with competitive kinetics (pK B =7.75). High anity competitive antagonism by MRS2279 was also observed at the human P2Y 1 receptor (pK B =8.10) stably expressed in 1321N1 human astrocytoma cells. Antagonism was speci®c for the P2Y 1 receptor since MRS2279 had no eect on activation of the human P2Y 2 , P2Y 4 , P2Y 6 , or P2Y 11 receptors by their cognate agonists. 4 MRS2279 also did not block the capacity of ADP to act through the Gi/adenylyl cyclase linked P2Y receptor of platelets to inhibit cyclic AMP accumulation. 5 In contrast, the P2Y 1 receptor is known to be obligatory in the process of ADP-induced platelet aggregation, and MRS2279 competitively inhibited ADP-promoted platelet aggregation with an apparent anity (pK B =8.05) similar to that observed at the human P2Y 1 receptor heterologously expressed in 1321N1 cells. 6 Taken together these results illustrate selective high anity antagonism of the P2Y 1 receptor by a non-nucleotide molecule that should prove useful for pharmacological delineation of this receptor in various tissues.

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Section: Resultsmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

2‐Chloro N⁶‐methyl‐(N)‐methanocarba‐2′‐deoxyadenosine‐3′,5′‐bisphosphate is a selective high affinity P2Y₁ receptor antagonist

Boyer

Adams

Ravi

et al. 2002

British J Pharmacology

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“…2), in which the 2′-methylene has been omitted and a 2-Cl has been added (to increase affinity). MRS 2286 was an antagonist at the turkey P2Y 1 receptor with an IC 50 value of 0.84 μM, and no agonist activity was observed [21]. Furthermore, the compound was inactive at P2X 1 receptors [20].…”

Section: Ribose-modified Nucleotide Analoguesmentioning

confidence: 93%

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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“…Ring expansion of the ribose in the 2-Cl-N 6 -Me series (in the form of an anhydrohexitol derivative, MRS 2283, IC 50 0.566 μM) and ring contraction (in the form of a cyclobutyl derivative, MRS 2264, IC 50 0.805 μM) has further emphasized the flexibility of substitution for the ribose moiety of P2Y receptor ligands (3). An acyclic modification of the ribose ring was found to preserve affinity at the P2Y 1 receptor (20). MRS 2286 (2-[2-(2-chloro-6-methylaminopurin-9-yl)-ethyl]-propane-1,3-bisoxy(diammonium-phosphate)) was an antagonist at the turkey erythrocyte P2Y 1 receptor with an IC 50 value of 0.84 μM, and no agonist affinity was observed.…”

Section: Ribose-modified Nucleoside and Nucleotide Analogues: P2y 1 Rmentioning

confidence: 99%

“…As a result, we substituted the ribose moiety in the antagonists series with a variety of cyclic (3) (carbocylics, smaller and larger rings, conformationally constrained rings) and acyclic moieties (20), without loss of affinity for the receptor.…”

Section: Ribose-modified Nucleoside and Nucleotide Analogues: P2y 1 Rmentioning

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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Acyclic Analogues of Deoxyadenosine 3‘,5‘-Bisphosphates as P2Y₁ Receptor Antagonists

Cited by 30 publications

References 27 publications

2‐Chloro N⁶‐methyl‐(N)‐methanocarba‐2′‐deoxyadenosine‐3′,5′‐bisphosphate is a selective high affinity P2Y₁ receptor antagonist

2‐Chloro N⁶‐methyl‐(N)‐methanocarba‐2′‐deoxyadenosine‐3′,5′‐bisphosphate is a selective high affinity P2Y₁ receptor antagonist

Structurally related nucleotides as selective agonists and antagonists at P2Y1 receptors

Ribose Modified Nucleosides and Nucleotides as Ligands for Purine Receptors

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Acyclic Analogues of Deoxyadenosine 3‘,5‘-Bisphosphates as P2Y1 Receptor Antagonists

Cited by 30 publications

References 27 publications

2‐Chloro N6‐methyl‐(N)‐methanocarba‐2′‐deoxyadenosine‐3′,5′‐bisphosphate is a selective high affinity P2Y1 receptor antagonist

2‐Chloro N6‐methyl‐(N)‐methanocarba‐2′‐deoxyadenosine‐3′,5′‐bisphosphate is a selective high affinity P2Y1 receptor antagonist

Structurally related nucleotides as selective agonists and antagonists at P2Y1 receptors

Ribose Modified Nucleosides and Nucleotides as Ligands for Purine Receptors

Contact Info

Product

Resources

About

Acyclic Analogues of Deoxyadenosine 3‘,5‘-Bisphosphates as P2Y₁ Receptor Antagonists

2‐Chloro N⁶‐methyl‐(N)‐methanocarba‐2′‐deoxyadenosine‐3′,5′‐bisphosphate is a selective high affinity P2Y₁ receptor antagonist

2‐Chloro N⁶‐methyl‐(N)‐methanocarba‐2′‐deoxyadenosine‐3′,5′‐bisphosphate is a selective high affinity P2Y₁ receptor antagonist