CP 376395

CP 376395 is a potent and selective Corticotropin releasing factor 1 (CRF1) receptor antagonist.

Signaling Pathways >> GPCR/G Protein >> CRFR

Research Areas >> Neurological Disease

CRF1[1]

CP 376395 fully antagonizes oCRF-stimulated adenylate cyclase activity in rat cerebral cortex and at human CRF1 receptors with an apparent Ki value of 12 nM, indicating antagonist functional activity. It is highly selective for the human CRF1 receptor subtype; affinity for the CRF2 receptor is >10000 nM. It shows affinities greater than 1 µM against 40 neurotransmitter receptor and ion channels[1].

In the CNS, systemically administered CP 376395 blocks the effects of both exogenous and endogenous CRF. Pretreatment with CP 376395 reverses the excitation of locus coeruleus neurons induced by icv CRF (3 µg) with an ID50 of completely blocked the enhanced startle response induced by icv CRF (1 µg) at 17.8 mg/kg, p.o. and partially blocked at 10 mg/kg, p.o. without significantly altering baseline startle. The attenuation of fear-potentiated startle is statistically significant at lower doses (0.32-3.2 mg/kg, p.o., with 62-83% blockade) and completely reversed by CP 376395 at 10 mg/kg, p.o[1].

Dogs: Four beagle dogs (two male and two female) weighing between 8 and 15 kg are administered 1 mesylate salt or CP 376395 hydrochloride salt (1.0 mg/kg) into the cephalic vein of the foreleg. The dosing solution for 1 is neat ethanol (15.4 mg/mL) and for CP 376395 is sterile saline at pH 2 (10 mg/mL). Oral dosing is conducted by gavage with drugs suspended in 0.1% methyl cellulose at pH 2. For the intravenous and fasted oral legs of the study, animals have last eaten approximately 21 h prior to drug administration and are permitted food and water approximately 3.5 h postdose. In the fed oral leg of the study, the animals are given one can of wet dog food 1 h before dosing. Blood samples are collected by venipuncture of the jugular vein prior to drug administration and at time points of 0.083 (i.v. only), 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12, and 24 h postdose, processed to obtain serum and stored frozen until the day of analysis[1].

[1]. Chen YL, et al. 2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists. J Med Chem. 2008 Mar 13;51(5):1385-92.

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