The corticotropin releasing hormone (CRH) receptor system and plays a central role in the response to stress in mammalian species. The CRH system consists of saturable, high-affinity CRH1 and CRH2 receptors and their endogenous ligands located in anatomically well-defined regions of the CNS and periphery with the CRH1 receptor mediating many CRH effects in the brain. CRH is involved in regulation of a number of normal functions and in the pathogenesis of a number of disorders including drug abuse, and other disorders of primary interest to NIDDK including the development of insulin resistance. CRH and its receptors are located peripherally in sympathetic nerve terminals and function as proinflammatory mediators in the gastrointestinal system. In the gut, CRH decreases stomach contractions and inhibits gastric emptying by activation of CRH2 receptors while increasing small intestinal and colonic motility by activating CRH1 receptors. Excessive chronic activation of the CRH system is involved in the pathogenesis of eating and gastrointestinal disorders. In a prior study of the latter, we described dramatic suppression of immobilization stress effects by the CRH1 antagonist antalarmin (see below) in a rat model of stomach ulcer, irritable bowel syndrome and inflammatory bowel disease. In some of our present studies involving the CRH system, we showed that antalarmin, a CRH1 antagonist has transient reinforcing effects in rhesus monkeys. We also described the first non-peptide CRH1 receptor ligand useful for imaging in vitro receptor binding. This compound, [76-Br]MJL-1-109-2, is a CRH1 receptor antagonist. We labeled it with 76-Br rendering it potentially suitable for positron emission tomography (PET) imaging of primate CRH1 receptors in vivo. The ability to measure CRH1 receptors in normal, conscious human subjects and in others with CRH1 receptor-related disorders will allow the development of new diagnostic and prognostic capabilities in disorders such as anxiety, depression and drug abuse. Quantitation of CRH1 receptors with PET will make possible to monitor the effects of drug treatment on these and other disorders. We recently reviewed some advances toward new tools to monitor stress using non-invasive PET imaging. Substance abuse and its consequences are also major stressors and contribute to many current societal and medical problems including a major role in the spread of acquired immune deficiency syndrome, drug-resistant tuberculosis and hepatitis. In order to gain further insight into the pathogenesis of stress-related disorders, to probe sites for possible intervention, and to develop potential treatments for these disorders, we have designed, synthesized and evaluated novel nonpeptide ligands which act on CRH receptors, cocaine receptors [DA transporter proteins] and the opioid receptors. Some of our results include: (1) pharmacological characterization of the effects of 3,4-methylenedioxymethamphetamine (Ecstasy) and its enantiomers on lethality, core temperature, and locomotor activity in singly housed and crowded mice as an animal model of rave parties (2) a study on delta-opioid receptor agonists as potential antidepressants (3) the development of a practical and high-yield synthesis of dihydromorphine from tetrahydrothebaine and efficient synthesis of (8S)-8-bromomorphide (4) the development of an enantioconvergent synthesis of (-)-(2R,5S)-1-allyl-2,5-dimethylpiperazine, an Intermediate to delta-opioid receptor ligands (5) the chemical synthesis of 5-phenylmorphan derivatives as probes of the opioid receptor system (6) a review on the development of neurochemical normalization agonist substitution) therapeutics for stimulant abuse: focus on the dopamine uptake inhibitor, GBR12909. We plan to further capitalize on current and developing knowledge of the CRH, dopamine and cocaine receptor systems through the development of nonpeptide drugs that either mimic or antagonize the effects of drugs and endogenous ligands at their recognition sites.
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