Design And Synthesis Of Drugs Acting On Central And Peri

Diabetes, Digestive, Kidney Diseases

Investigators

Linked publications & trials

Abstract

The design, synthesize and evaluation of novel nonpeptide ligands has been continued to provide tools for study of the corticotropin releasing hormone (CRH) receptor system receptors, cocaine receptors [DA transporter proteins] and the opioid receptors. These studies are providing further insight into the pathogenesis of stress-related disorders and drug abuse, and potential treatments for these disorders. The CRH system consists of saturable, high-affinity CRH1 and CRH2 receptors and their endogenous ligands located in anatomically well-defined regions of the central nervous system (CNS) and periphery with the CRH1 receptor mediating many CRH effects in the brain. This hormone is involved in regulation of a number of normal functions and in the pathogenesis of a number of disorders of primary interest to NIDDK including the development of insulin resistance. Excessive chronic activation of the CRH system is involved in the pathogenesis of eating and gastrointestinal disorders and many other disorders including drug abuse. We have studied antalarmin, R121919 and MJL-1-109.2 (CRHR1 receptor antagonist) and found that these compounds suppress self administration of alcohol in alcohol dependent rats but not in nondependent rats. Our findings suggest that CRHR1 antagonists may have utility in preventing alcohol withdrawal stress related human relapse to alcohol drinking and are complimentary to our earlier finding that antalarmin suppresses stress induced relapse to compulsive food seeking in a rat model. Earlier, we introduced LWH63 as a sub nM affinity CRHR1 receptor ligand. We have now tritiated this compound to high specific activity as a potential nonpeptide primary ligand for CRHR1 receptors in order to eliminate problems inherent in the use of high specific activity peptide ligands. From the foregoing, it is clear that CRH1 antagonists such as antalarmin can be valuable research tools and potential medications. Many opportunities exist for exploitation of current and developing knowledge of the CRH system through the development of nonpeptide drugs that either mimic or antagonize the effects of CRH and the other endogenous ligands at their recognition sites. We plan to further exploit current and developing knowledge of the CRH, opioid and biogenic amine systems through the development of nonpeptide drugs that either mimic or antagonize the effects of drugs and endogenous ligands at their recognition sites.