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Dunn PM, Kim HS, Jacobson KA, et al. Northern Ring Conformation of Methanocarba-Adenosine 5'-Triphosphate Required for Activation of P2X Receptors. Drug Dev Res. 2004;61(4):227-232doi: 10.1002/ddr.10381.
Dunn, P. M., Kim, H. S., Jacobson, K. A., & Burnstock, G. (2004). Northern Ring Conformation of Methanocarba-Adenosine 5'-Triphosphate Required for Activation of P2X Receptors. Drug development research, 61(4), 227-232. https://doi.org/10.1002/ddr.10381
Dunn, Philip M, et al. "Northern Ring Conformation of Methanocarba-Adenosine 5'-Triphosphate Required for Activation of P2X Receptors." Drug development research vol. 61,4 (2004): 227-232. doi: https://doi.org/10.1002/ddr.10381
Dunn PM, Kim HS, Jacobson KA, Burnstock G. Northern Ring Conformation of Methanocarba-Adenosine 5'-Triphosphate Required for Activation of P2X Receptors. Drug Dev Res. 2004 Apr;61(4):227-232. doi: 10.1002/ddr.10381. Epub 2004 Sep 22. PMID: 22833693; PMCID: PMC3402081.
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Drug Dev Res. 2004 Apr;61(4):227-232. doi: 10.1002/ddr.10381. Epub 2004 Sep 22.

Northern Ring Conformation of Methanocarba-Adenosine 5'-Triphosphate Required for Activation of P2X Receptors.

Drug development research

Philip M Dunn, Hak Sung Kim, Kenneth A Jacobson, Geoffrey Burnstock

Affiliations

  1. Autonomic Neuroscience Institute, Royal Free and University College Medical School, London, United Kingdom.

PMID: 22833693 PMCID: PMC3402081 DOI: 10.1002/ddr.10381

Abstract

Strategy, Management and Health PolicyEnabling Technology, Genomics, ProteomicsPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I-III Regulatory, Quality, ManufacturingPostmarketing Phase IVReplacement of the ribose moiety of adenosine 5'-triphosphate (ATP) with a carbocyclic ring constrained in either the Northern (N) or Southern (S) conformation produces agonists with widely differing activities at P2Y receptors (Kim et al. [2002] J Med Chem 45:208-218). We have used whole cell patch clamp recording to investigate the agonist activity of these two methanocarba analogs of ATP at four different P2X receptors (P2X(1), P2X(2), P2X(3), and P2X(2/3)). On dorsal root ganglion neurons, (N) methanocarba-ATP ((1'S,2'R,3'S,4'R,5'S)-4-(6-amino-9H-purin-9-yl)-1-[triphosphoryloxymethyl] bicyclo[ 3.1.0]hexane-2,3-diol; MRS 2340) activated rapidly-desensitizing (P2X(3)) and slowly-desensitizing (P2X(2/3)) receptors with a similar potency to ATP. In contrast, (S) methanocarba-ATP ((±)-5-(6-amino-9H-purin-9-yl)-1-[triphosphoryloxymethyl] bicycle [3.1.0]hexane-2,3-diol MRS 2312) was devoid of agonist activity. On nodose ganglion neurones, that express mainly P2X(2/3) receptors, ATP evoked a slowly desensitizing inward current with an EC(50) value of 26 μM. MRS 2340 was an effective agonist, but less potent than ATP, while MRS 2312 at concentrations up to 100 μM produced a barely detectable response. On mammalian cell lines expressing recombinant hP2X(1) and hP2X(2) receptors, MRS 2340 evoked inward currents similar in amplitude to those produced by the same concentration of ATP or α,β-mATP. In contrast, MRS 2312 failed to give a detectable response. Although the conformation of the ribose affects agonist activity at P2Y receptors, there is a strong requirement for the (N) conformation for the activation of these P2X receptors. Furthermore, the region of the agonist binding site that accommodates the ribose moiety appears to be highly conserved among different P2X receptors. Drug Dev Res 61:227-232, 2004.

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