PMID- 18031798
OWN - NLM
STAT- MEDLINE
DCOM- 20080508
LR  - 20240315
IS  - 0091-3057 (Print)
IS  - 1873-5177 (Electronic)
IS  - 0091-3057 (Linking)
VI  - 88
IP  - 4
DP  - 2008 Feb
TI  - MPZP: a novel small molecule corticotropin-releasing factor type 1 receptor 
      (CRF1) antagonist.
PG  - 497-510
AB  - 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.
FAU - Richardson, Heather N
AU  - Richardson HN
AD  - Committee on the Neurobiology of Addictive Disorders, The Scripps Research 
      Institute, La Jolla, 92037 California, USA.
FAU - Zhao, Yu
AU  - Zhao Y
FAU - Fekete, Eva M
AU  - Fekete EM
FAU - Funk, Cindy K
AU  - Funk CK
FAU - Wirsching, Peter
AU  - Wirsching P
FAU - Janda, Kim D
AU  - Janda KD
FAU - Zorrilla, Eric P
AU  - Zorrilla EP
FAU - Koob, George F
AU  - Koob GF
LA  - eng
GR  - R01 AA012602-12/AA/NIAAA NIH HHS/United States
GR  - AA12602/AA/NIAAA NIH HHS/United States
GR  - DK26741/DK/NIDDK NIH HHS/United States
GR  - P60 AA006420-29/AA/NIAAA NIH HHS/United States
GR  - R37 AA008459/AA/NIAAA NIH HHS/United States
GR  - AA08459/AA/NIAAA NIH HHS/United States
GR  - R01 AA012602/AA/NIAAA NIH HHS/United States
GR  - R01 AA008459/AA/NIAAA NIH HHS/United States
GR  - P01 DK026741/DK/NIDDK NIH HHS/United States
GR  - P01 DK026741-33/DK/NIDDK NIH HHS/United States
GR  - P60 AA006420/AA/NIAAA NIH HHS/United States
GR  - R01 AA008459-21/AA/NIAAA NIH HHS/United States
GR  - P50 AA006420/AA/NIAAA NIH HHS/United States
GR  - AA06420/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20071023
PL  - United States
TA  - Pharmacol Biochem Behav
JT  - Pharmacology, biochemistry, and behavior
JID - 0367050
RN  - 0 (Anti-Anxiety Agents)
RN  - 0 (CRF receptor type 2)
RN  - 0 (Central Nervous System Depressants)
RN  - 0 (Ligands)
RN  - 0 
      (N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo(1,5-a)pyrimidin-7-amine)
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, Corticotropin-Releasing Hormone)
RN  - 3K9958V90M (Ethanol)
RN  - 5CLY6W2H1M (CRF receptor type 1)
SB  - IM
MH  - Administration, Inhalation
MH  - Alcohol Drinking/psychology
MH  - Animals
MH  - *Anti-Anxiety Agents
MH  - Anxiety/psychology
MH  - Behavior, Animal/drug effects
MH  - Central Nervous System Depressants/administration & dosage/blood/pharmacology
MH  - Conditioning, Operant/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Ethanol/administration & dosage/blood/pharmacology
MH  - Ligands
MH  - Male
MH  - Pyrimidines/*pharmacology
MH  - Rats
MH  - Receptors, Corticotropin-Releasing Hormone/*antagonists & inhibitors/drug 
      effects/metabolism
MH  - Self Administration
PMC - PMC3319109
MID - NIHMS38660
EDAT- 2007/11/23 09:00
MHDA- 2008/05/09 09:00
PMCR- 2012/04/04
CRDT- 2007/11/23 09:00
PHST- 2007/08/25 00:00 [received]
PHST- 2007/10/13 00:00 [revised]
PHST- 2007/10/17 00:00 [accepted]
PHST- 2007/11/23 09:00 [pubmed]
PHST- 2008/05/09 09:00 [medline]
PHST- 2007/11/23 09:00 [entrez]
PHST- 2012/04/04 00:00 [pmc-release]
AID - S0091-3057(07)00321-8 [pii]
AID - 10.1016/j.pbb.2007.10.008 [doi]
PST - ppublish
SO  - Pharmacol Biochem Behav. 2008 Feb;88(4):497-510. doi: 10.1016/j.pbb.2007.10.008. 
      Epub 2007 Oct 23.