Faculty Collaboration Database

MPZP: a novel small molecule corticotropin-releasing factor type 1 receptor (CRF1) antagonist. Pharmacol Biochem Behav 2008 Feb;88(4):497-510

Date

11/23/2007

Pubmed ID

18031798

Pubmed Central ID

PMC3319109

DOI

10.1016/j.pbb.2007.10.008

Scopus ID

2-s2.0-37249042346 (requires institutional sign-in at Scopus site)   85 Citations

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.

Author List

Richardson HN, Zhao Y, Fekete EM, Funk CK, Wirsching P, Janda KD, Zorrilla EP, Koob GF

Author

Eva M. Fekete PhD Research Scientist I in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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