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Cyclic Dimers Of C-terminal γ2-MSH Analogs As Selective Antagonists Of The Human Sensory Nerve-Specific Receptor (SNSR-4)

  • Ralf Schmidt
  • Joanne Butterworth
  • Dajan O'Donnell
  • V. Santhakumar
  • Mirek Tomaszewski
Part of the Advances in Experimental Medicine and Biology book series (volume 611)

Introduction

Sensory nerve-specific G-protein coupled receptors (SNSR) have been implicated in the transmission of pain based on their unique expression and distribution in CNS and periphery. Human SNSRs are potently activated by pro-enkephalin A gene products such as BAM-22 and BAM(8–22) whereas γ2-MSH derived sequences are the most potent activators of the rat receptor [1,2]. Both families of peptides produce a pro-nociceptive effect in various animal models of pain suggesting that a SNSR antagonist might have potential as an analgesic agent. The low homology between the human and rat receptor and widely different structure-activity relationships (SAR) of the activating ligands prompted the search for selective antagonists for either SNSR.

Starting from the most potent rat receptor agonist, the N-terminal fragment γ2-MSH(6–12), extensive SAR studies were performed yielding linear and cyclic analogs with exclusively agonist activity at the rat receptor while being completely inactive...

Keywords

Wang Resin Diaminobutyric Acid Antagonist Potency Asymmetric Dimer Positional Amino Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Lembo, P.M.C., et al. Nature Neuroscience 5, 2017#x2013;209 (2002).CrossRefGoogle Scholar
  2. 2.
    Grazzini, E., et al. Proc. Natl. Acad. Sci. USA 101, 7175–7180 (2004).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Ralf Schmidt
    • 1
  • Joanne Butterworth
    • 2
  • Dajan O'Donnell
    • 3
  • V. Santhakumar
    • 1
  • Mirek Tomaszewski
    • 2
  1. 1.Department of Medicinal ChemistryAstraZeneca R&D MontrealCanada
  2. 2.Department of PharmacologyAstraZeneca R&D MontrealCanada
  3. 3.Department of Molecular ScienceAstraZeneca R&D MontrealCanada

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