Medicinal Chemistry of Drugs Acting on CRH Receptors

National Institute On Drug Abuse

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Abstract

The stress system is well known to play an important role in relapse to drug abuse and excessive eating and is largely controlled by corticotropin releasing hormone receptors (CRHR) and their endogenous ligands. The CRH system is also involved in the progression of an Alzheimer's-like disease in mice that is accelerated by psychosocial stressors. During the reporting period, we studied the question of whether nonpeptide CRH antagonists antalarmin and R121919 could inhibit the formation of plaque deposition in an Alzheimer's disease isolation mouse model. We used TG2576 mice, a commonly used mouse model of Alzheimers. We found that 6-month chronic administration of antalarmin reduced plaque deposition in the stressed and unstressed mice. We conclude that antagonism of the CHR stress system can mitigate the advance of Alzheimer's-like disease in this model and that CRH antagonists may be useful as medications to blunt the advance of Alzheimer's disease.