Quizartinib synthesis br Conclusion The results of the prese
Conclusion The results of the present study suggest that blockade of CRF1 and CRF2 receptors in the BLA and CeA reduces the duration of TI behavior, probably due to decreased fear and/or anxiety. It is possible that this effect of specific CRF receptor antagonists can occur by reduction of endogenous activation of CRF induced by TI. Further, it was not due to altered spontaneous motor activity, which may non-specifically affect TI behavior. Our findings support the Quizartinib synthesis that increased activation of CRF receptors, CRF1 and CRF2, in the BLA and CeA is responsible for anxiogenic and fearful responses.
Conflicts of interest
Acknowledgements The authors would like to thank Patrícia Adriana Basile for her technical assistance. This work was supported by CAPES/PROEX, FAPESP (2010/10936-5). R.L. Spinieli is the recipient of a Master’s degree scholarship from CAPES and C.R.A. Leite-Panissi received research grants from the CNPq (# 307383/2012-1).
Introduction Major depression is a complex and recurrent lifelong illness, characterized by repeated periods of exacerbation and remission. Despite the number of treatments available (which focus mainly on addressing modulation of monoamine neurotransmitters), significant unmet needs remain in terms of efficacy, onset of effect, and tolerability. Currently-available antidepressant drugs take 6–8weeks to exert their effect, and ∼30% of patients are non-responders; moreover drug-induced side effects reduce patient compliance. Extensive attempts have been made to identify the relevant biological targets contributing to the main pathophysiological mechanisms of anxiety and depressive disorders with the aim of getting more efficacious and safer treatments with rapid relief of symptoms. It is well-known that corticotropin-releasing factor (CRF) exerts its biological functions through binding to type-1 (CRF1) and/or type-2 (CRF2) receptors. Several clinical evidences suggest the association of a high level of CRF and the onset of anxiety and depressive disorders.2, 3, 4, 5, 6, 7 Significant contributions have been made in the past two decades by several pharmaceutical research groups to discover non-peptide CRF1 receptor antagonists as a potential treatment for stress-related illnesses (including depression). 7H-Pyrrolo[2,3-d]pyrimidine (CP-154,526) as well as pyrazolo[1,5-a]pyrimidine (R121919) and pyrazolo[1,5-a][1,3,5]triazine (DMP-696) are among the first and most representative compounds identified. In an effort to discover structurally novel CRF1 receptor antagonists exhibiting improved in vivo profiles, many scaffolds have been designed and synthesized. In this report, we describe novel bicyclic core CRF1 antagonists 2–3 (Fig. 1). These are designed based on the tricyclic core CRF1 antagonist 1 reported in our previous study. Cleavage of the C-ring of the tricyclic core structure consisting of A-, B- and C-rings resulted in a novel bicyclic core structure consisting of A- and B-rings (Fig. 1). Bicyclic core structures consisting of B- and C-rings were previously reported with dihydroimidazoles, dihydropyrrolopyrimidines,11, 12 tetrahydroimidazopyrimidines and imidazoimidazoles while the bicyclic core structures in this report consist of A- and B-rings.