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

摘要

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 (CRF1) system are hypothesized to underlie many stress-related disorders. Modulation of the CRF1 system by non-peptide antagonists currently is being explored as a therapeutic approach for anxiety disorders and alcohol dependence. Here, we describe a new hydrophilic (cLogP ~2.95) small molecule, non-peptide CRF1 antagonist with high affinity (Ki = 4.9 nM) and specificity for CRF1: N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethylpyrazolo[1,5-a] pyrimidin-7-amine (MPZP). The compound was systemically administered to adult male rats in two behavioral models dependent on the CRF1 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 underscore the significance of the CRF1 system in the psychopathology of anxiety disorders and alcohol dependence and introduce a promising new compound for further development in the treatment of alcohol dependence and stress-related disorders.