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

Authors
Journal
Pharmacology Biochemistry and Behavior
0091-3057
Publisher
Elsevier
Publication Date
Volume
88
Issue
4
Identifiers
DOI: 10.1016/j.pbb.2007.10.008
Keywords
  • Corticotropin-Releasing Factor
  • Corticotropin-Releasing Hormone
  • Receptor
  • Crf1
  • Antagonist
  • Mpzp
  • Alcohol
  • Defensive Burying
  • Anxiety
  • Dependence
  • Binding
  • Autoradiography
Disciplines
  • Medicine

Abstract

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 ∼ 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.

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