Hyperactivation of corticotropin releasing factor (CRF) in stress response system pathways is linked to stress-related psychopathology. The CRF receptor antagonists, particularly CRF receptor 1, have been proposed as novel therapeutic agents for depression, anxiety and addiction disorders. CRF is a 41 amino acid containing peptide released from the Para ventricular nucleus (PVN) of the hypothalamus. It is a critical to the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. CRF mediates is actions through two G protein-coupled receptors: CRF receptor 1 (CRFR1) and CRF receptor 2 (CRFR2). While CRFR1-mutant mice display a depleted stress response and display anxiolytic-like behavior, CRFR2-mutant mice are hypersensitive to stress and display anxiogenic-like behavior. Thus CRFR1 antagonists may provide novel therapeutic agents for treating anxiety, depression and addictive disorders.Numerous peptide and non-peptide molecules have been shown to inhibit CRF mediated stress disorders through CRFR1. In our studies, we have synthesized several new 5-(alkylthio)-4-(arylamino)pyrimidine derivatives as potential CRFR1 antagonists. These derivatives were analyzed for their effect on mRNA expression of several markers of psychopathology including; CRF1, serotonin transporter (SERT), the cAMP response element-binding (CREB), monoamine oxidase-A (MAO-A), dopamine transporter (DAT), dopamine �-hydroxylase (DBH) and cAMP levels in aT3-1 pituitary mouse cell line and compared with Antalarmin. Some of the derivatives showed comparable results with Antalarmin. These compounds will be also evaluated for their binding affinities to CRF1 receptors and those showing comparable parameters of interaction with CRFR1 as Antalarmin will be further evaluated in animal studies.

Substitued 5-(alkylthio)-4-(arylamino)pyrimidine derivatives as corticotropin releasing factor receptor 1 (CRFR1) antagonists

244th National Meeting (2012)

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