P1 and P2 Purine and Pyrimidine Receptor Ligands

Jacobson, Ken; Knutsen, Lars J. S.

doi:10.1007/978-3-662-09604-8_6

Cited by 64 publications

(119 citation statements)

References 153 publications

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“…1,2 Although molecular modeling of adenosine agonists has been carried out, 30 there has been little direct evidence for a conformational preference of the ribose ring in the receptor binding site. The furanose ring of nucleosides and nucleotides in solution is known to exist in a rapid, dynamic equilibrium between a range of Northern ( 2 E → 3 T 2 → 3 E) and opposing Southern ( 2 E → 2 T 3 → 3 E) conformations as defined in the pseudorotational cycle.…”

Section: Discussionmentioning

confidence: 99%

“…The parent adenosine analogues are potent agonists at either A 1 (cyclopentyl) or A 3 (3-iodobenzyl) receptors. 1 The N 6 -(3-iodobenzyl)…”

Section: Chemical Synthesismentioning

confidence: 99%

“…The parent adenosine analogues are potent agonists at either A 1 (cyclopentyl) or A 3 (3-iodobenzyl) receptors. 1 The N 6 -(3-iodobenzyl) substitution is present in the selective A 3 agonist IB-MECA and also promotes A 3 receptor affinity in the 5′-hydroxy series. 25 2,6-Dichloropurine, 10, was condensed with the cyclopentyl derivative, 11, 18 using the Mitsunobu reaction, followed by substitution at the 6-position and deprotection to give 8c or 9c.…”

Section: Chemical Synthesismentioning

confidence: 99%

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Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

et al. 2000

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Adenosine receptor agonists have cardioprotective, cerebroprotective, and antiinflammatory properties. We report that a carbocyclic modification of the ribose moiety incorporating ring constraints is a general approach for the design of A 1 and A 3 receptor agonists having favorable pharmacodynamic properties. While simple carbocyclic substitution of adenosine agonists greatly diminishes potency, methanocarba-adenosine analogues have now defined the role of sugar puckering in stabilizing the active adenosine receptor-bound conformation and thereby have allowed identification of a favored isomer. In such analogues a fused cyclopropane moiety constrains the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle. In binding assays at A 1 , A 2A , and A 3 receptors, (N)-methanocarba-adenosine was of higher affinity than the (S)-analogue, particularly at the human A 3 receptor (N/S affinity ratio of 150). (N)-Methanocarba analogues of various N 6 -substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A 1 or A 3 receptors, respectively, were synthesized. The N 6 -cyclopentyl derivatives were A 1 receptor-selective and maintained high efficacy at recombinant human but not rat brain A 1 receptors, as indicated by stimulation of binding of [ 35 S]GTP-γ-S. The (N)-methanocarba-N 6 -(3-iodobenzyl)adenosine and its 2-chloro derivative had K i values of 4.1 and 2.2 nM at A 3 receptors, respectively, and were highly selective partial agonists. Partial agonism combined with high functional potency at A 3 receptors (EC 50 < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y 1 receptors, at least three adenosine receptors favor the ribose (N)-conformation.In work designed to develop potent and selective agents, the structure-activity relationships of adenosine derivatives as ligands (principally agonists) at the four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) have been explored extensively. Adenosine receptor agonists 1,2 are being studied for their potential use as antiarrhythmic, 3 antinociceptive, 4 and antilipolytic 5,6 agents (A 1 subtype); as cerebroprotective 7 and cardioprotective 8 agents (A 1 and A 3 subtypes); and as hypotensive 9 and antipsychotic 10 agents (A 2A subtype).* Address correspondence to Dr. Kenneth A. Jacobson, Chief, Molecular Recognition Section, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. Tel: (301) In general, for adenosine agonists, numerous modifications of the N 6 -position with cycloalkyl and other hydrophobic moieties provide selectivity for A 1 receptors, although the affinities of these N 6 -substituted adenosine derivatives (e.g. N 6 -cyclopentyl) at A 3 receptors are often intermediate between their respective A 1 and A 2A affinities. 1 Structurally, few ribose modifications, other than amide substitution at the 5′-position, are tolerated in adenosine agonists. An intact f...

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Section: Discussionmentioning

confidence: 99%

“…The parent adenosine analogues are potent agonists at either A 1 (cyclopentyl) or A 3 (3-iodobenzyl) receptors. 1 The N 6 -(3-iodobenzyl)…”

Section: Chemical Synthesismentioning

confidence: 99%

Section: Chemical Synthesismentioning

confidence: 99%

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Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

et al. 2000

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“…Modulation of adenosine receptors (P1) and nucleotide (P2) receptors by selective agonists and antagonists [1,2] has the potential for the treatment of a wide range of diseases, including those of the cardiovascular, inflammatory, and central nervous systems. Extracellular nucleotides, principally ATP, ADP, UTP, and UDP, act through two families of membrane-bound P2 receptors: P2Y subtypes, all of which are G protein-coupled receptors (GPCRs), generally coupled to phospholipase C (PLC); and P2X subtypes, ligandgated ion channels.…”

Section: Introductionmentioning

confidence: 99%

“…Extracellular nucleotides, principally ATP, ADP, UTP, and UDP, act through two families of membrane-bound P2 receptors: P2Y subtypes, all of which are G protein-coupled receptors (GPCRs), generally coupled to phospholipase C (PLC); and P2X subtypes, ligandgated ion channels. Though the endogenous ligand for P2X receptors is generally ATP, P2Y receptors are activated by adenine and/or uracil nucleotides [2]. Agonists of P2 receptors are almost exclusively nucleosides and nucleotides, respectively, whereas antagonists of these receptors are structurally more diverse [1].…”

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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Potent P2X₇ receptor antagonists: Tyrosyl derivatives synthesized using a sequential parallel synthetic approach

Ravi¹,

Kertesy²,

Dubyak³

2001

Drug Development Research

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Novel analogs of 1-(,-bis[5-isoquinolinesulfonyl]-N-methyl-L-tyrosyl)-4-phenylpiperazine (KN-62,1) were synthesized and found to be potent antagonists in a functional assay, inhibition of ATP-induced K efflux in HEK293 cells expressing recombinant human P2X receptors. Antagonism of murine P2X receptors was also observed. The analogs consisted of L-tyrosine derivatives, of the general structure R-Tyr(OR)-piperazinyl-R, in which three positions were systematically varied in structure through facile acylation reactions. Each of the three positions was optimized in sequence through parallel synthesis alternating with biological evaluation, leading to the identification and optimization of potent P2X antagonists. The optimal groups at R were found to be large hydrophobic groups, linked to the α-amino position through carbamate, amide, or sulfonamide groups. The benzyloxycarbonyl (Cbz) group was preferred over most sulfonamides and other acyl groups examined, except for quinoline sulfonyl. At R, an arylsulfonate ester was preferred, and the order of potency was p-tolyl, p-methoxyphenyl, phenyl > α-naphthyl, β-naphthyl. A benzoyl ester was of intermediate potency. Aliphatic esters and carbonate derivatives at the tyrosyl phenol were inactive, while a tyrosyl O-benzyl ether was relatively potent. The most potent P2X receptor antagonists identified in this study contained Cbz at the R position, an aryl sulfonate at the R position, and various acyl groups at the R position. At R, -butyloxycarbonyl- and benzoyl groups were preferred. The opening of the piperazinyl ring to an ethylene diamine moiety abolished antagonism. In concentration-response studies, a di-isoquinolinyl, Boc derivative, (MRS2306), displayed an IC value of 40 nM as an antagonist of P2X receptor-mediated ion flux and was more potent than the reference compound . N-Cbz, Boc-piperazinyl derivatives, (MRS2317), (MRS2326), and (MRS2409) were less potent than, with IC values of 200-300 nM.

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P1 and P2 Purine and Pyrimidine Receptor Ligands

Cited by 64 publications

References 153 publications

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

Structurally related nucleotides as selective agonists and antagonists at P2Y1 receptors

Potent P2X₇ receptor antagonists: Tyrosyl derivatives synthesized using a sequential parallel synthetic approach

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P1 and P2 Purine and Pyrimidine Receptor Ligands

Cited by 64 publications

References 153 publications

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

Structurally related nucleotides as selective agonists and antagonists at P2Y1 receptors

Potent P2X7 receptor antagonists: Tyrosyl derivatives synthesized using a sequential parallel synthetic approach

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Potent P2X₇ receptor antagonists: Tyrosyl derivatives synthesized using a sequential parallel synthetic approach