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MPZP: A novel small molecule corticotropin-releasing factor type 1 receptor (CRF1) antagonist

Academic Article
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Overview

authors

  • Richardson, H. N.
  • Zhao, Y.
  • Fekete, E. M.
  • Funk, C. K.
  • Wirsching, P.
  • Janda, Kim
  • Zorrilla, Eric
  • Koob, George

publication date

  • February 2008

journal

  • Pharmacology, Biochemistry and Behavior  Journal

abstract

  • The extrahypothalamic stress peptide corticotropin-releasing factor (CRF) system is an important regulator of behavioral responses to stress. Dysregulation of CRF and the CRF type 1 receptor (CRF(1)) system is hypothesized to underlie many stress-related disorders. Modulation of the CRF(1) system by non-peptide antagonists currently is being explored as a therapeutic approach for anxiety disorders and alcohol dependence. Here, we describe a new, less hydrophilic (cLogP approximately 2.95), small molecule, non-peptide CRF(1) antagonist with high affinity (K(i)=4.9 nM) and specificity for CRF(1) receptors: N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5-a] pyrimidin-7-amine (MPZP). The compound was systemically administered to adult male rats in two behavioral models dependent on the CRF(1) system: defensive burying (0, 5, 20 mg/kg, n=6-11 for each dose) and alcohol dependence (0, 5, 10, 20 mg/kg, n=8 for each self-administration group). Acute administration of MPZP reduced burying behavior in the defensive burying model of active anxiety-like behavior. MPZP also attenuated withdrawal-induced excessive drinking in the self-administration model of alcohol dependence without affecting nondependent alcohol drinking or water consumption. The present findings support the proposed significance of the CRF(1) system in anxiety and alcohol dependence and introduce a promising new compound for further development in the treatment of alcohol dependence and stress-related disorders.

subject areas

  • Administration, Inhalation
  • Alcohol Drinking
  • Animals
  • Anti-Anxiety Agents
  • Anxiety
  • Behavior, Animal
  • Central Nervous System Depressants
  • Conditioning, Operant
  • Dose-Response Relationship, Drug
  • Ethanol
  • Ligands
  • Male
  • Pyrimidines
  • Rats
  • Receptors, Corticotropin-Releasing Hormone
  • Self Administration
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Research

keywords

  • CRF1
  • MPZP
  • alcohol
  • antagonist
  • anxiety
  • autoradiography
  • binding
  • corticotropin-releasing factor
  • corticotropin-releasing hormone
  • defensive burying
  • dependence
  • receptor
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Identity

PubMed Central ID

  • PMC3319109

International Standard Serial Number (ISSN)

  • 0091-3057

Digital Object Identifier (DOI)

  • 10.1016/j.pbb.2007.10.008

PubMed ID

  • 18031798
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Additional Document Info

start page

  • 497

end page

  • 510

volume

  • 88

issue

  • 4

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