In order to gain further insight into the pathogenesis of stress-related disorders and drug abuse, 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 corticotropin releasing hormone (CRH) receptor system receptors, cocaine receptors [DA transporter proteins] and the opioid receptors. 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. This hormone is involved in regulation of a number of normal functions and in the pathogenesis of a number of disorders 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. The treatment and prevention of the abuse of narcotic drugs and the psychomotor stimulants cocaine and methamphetamine are critical areas from a health and societal viewpoint. We have made advances in these areas and have originated a medication for treatment of psychomotor stimulant abuse that has now entered phase 2 clinical testing. We have also introduced several related drugs as later generation candidates for clinical trials that can be converted to ultra long-acting prodrugs. Earlier, we showed that one dose of one of these prodrugs virtually abolished cocaine self-administration in rhesus monkeys for about one month. We also studied the effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys and determined the relationship to transporter occupancy as measured by PET neuroimaging. Some of our other results include: (1) pharmacological characterization of the role of the 5-HT2A receptor on hyperlocomotor activity and hyperthermic effects produced by 3,4-methylenedioxymethamphetamine (Ecstasy) (2) Study of the effects of the delta-opioid receptor agonist SNC80 on learning and its antidepressant-like effects in rats (3) the development of a practical chemical synthesis of optically pure N-norbremazocine enantiomers as intermediates for a novel and facile preparation of bremazocine enantiomers (4) elucidation of the behavioral, adrenal and sympathetic responses to long term administration of an oral CRH receptor antagonist in a primate stress paradigm (5) the chemical synthesis of novel 5-phenylmorphan derivatives as probes of the opioid receptor system. A review, Analgesic research at NIH: State of the Art 1930?s to State of the Art 2002 was published. A review was also published on nonpeptide CRH type 1 receptor antagonists as medications and imaging agents. We plan to further exploit 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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