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  • In a cell based functional assay the antagonist properties o

    2019-09-10

    In a cell-based functional assay, the antagonist properties of were assessed by measuring inhibition of CRF-stimulated cyclic adenosine monophosphate (cAMP) production in human Y-79 retinoblastoma cells. produced a concentration-dependent inhibition of CRF (1nM)-induced cAMP production with an IC value of 1.2±0.2nM, and completely suppressed CRF-stimulated cAMP production at higher concentrations, indicating that this 5,7-dihydroxychromone behaved as an antagonist. In conclusion, pyrazinone-based compounds containing novel groups within the upper R substituent () were synthesized and evaluated as CRF receptor antagonists. It was found that a variety of larger R groups could be accommodated in this region of the CRF receptor while still maintaining good CRF receptor binding affinity. In particular, the potency of the 3-pyridyl substituted carbamate indicated that a limited degree of polarity was tolerated within the R substituent while still maintaining excellent potency. Further investigation is necessary to fully characterize the size and scope of substituents and functionality that can be incorporated into the R substituent in this pyrazinone chemotype.
    Introduction Individuals display differences in vulnerability to the deleterious effects of stress which may be due to genetic factors, early life experiences or exposure to major life stressors. Corticotropin-releasing factor (CRF) is a key stress hormone secreted by the paraventricular nucleus of the hypothalamus which initiates the hypothalamic-pituitary adrenal axis and is thought to contribute to variability to stress susceptibility [12], [29]. CRF evokes its effects by activating the G-protein coupled CRF1 and CRF2 receptors (CRFR1 and CRFR2)[11], which are critical for the development and integration of physiological responses to stressful stimuli. CRFR1 is highly expressed throughout the brain, particularly in regions associated with affective, stress and nociceptive circuitries [21]. Indeed, CRFR1 null mice exhibit fewer anxiety-like behaviors [27]. Central expression of CRFR2 appears to be more restricted but has been detected in the hypothalamus, the amygdala, the nucleus of the solitary tract and raphe nucleus [17] and knockout of CRFR2 is anxiogenic [1]. Intracellularly, activation of extracellular signal regulated kinases (ERK)1/2 signal transduction mediators have been proposed to play a role in stress [19] and have been linked with the actions of CRF [18], [24]. The stress-sensitive Wistar Kyoto (WKY) rat is a genetic animal model of irritable bowel syndrome (IBS) [22] which displays enhanced anxiety-like behaviors upon stress exposure [13], [16]. Moreover, WKY rats display increased cortical cFos expression [6] and central CRFR1 activation in response to colorectal distension [8]. Given the central role played by CRF in the regulation of anxiety and depression [2], [33], examining alterations in receptor expression relative to phenotypic changes may provide new insights to the complex interactions between stress-susceptibility and disease. This study examines CRFR1 and CRFR2 expression in the hypothalamus, prefrontal and frontal cortices (PFC and FC), amygdala and hippocampus, brain regions implicated in stress coping behaviors, under basal conditions and following exposure to the acute psychological stressor of an open field trial in stress-sensitive WKY and Sprague Dawley (SD) controls. Moreover, activation of ERK was also determined in these rat strains.
    Materials and methods
    Results
    Discussion We and others have previously reported behavioral patterns exhibited by WKY rats which are consistent with the heightened levels of anxiety, including an exaggerated secretion of stress hormones [22], reduced time exploring the OF arena and increased defecation rates during a trial [14]. The data presented in this manuscript illustrate how the genetic make-up of stress-sensitive WKY rats results in alterations in central CRF receptor expression and the modulation of downstream signaling cascades, both under basal conditions and following challenge with an acute stressor. Strain differences in expression of CRFR1 between WKY rats and their low-anxiety SD comparators were noted in the hypothalamus where expression was decreased and also in the hippocampus, where expression was increased. Moreover, strain differences in CRFR1 expression following exposure to an acute psychological stressor were noted in the hypothalamus, the FC and the hippocampus illustrating that the stress-sensitive behavioral phenotype exhibited by WKY rats may have a molecular basis.