Drug Design/Synthesis--Central/Peripheral Tissue Action

Diabetes, Digestive, Kidney Diseases

Investigators

Linked publications & trials

Abstract

We have continued to design, synthesize and evaluate novel nonpeptide ligands that act on corticotropin releasing hormone (CRH) receptor system receptors, cocaine receptors [DA transporter proteins] and the opioid receptors as tools for study of these systems. These studies are providing further insight into the pathogenesis of stress-related disorders and drug abuse, and potential treatments for these disorders. In addition, we have begun a program to synthesize interleukin-6 receptor antagonists as research tools and potential drugs. 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, a CHR1 receptor antagonist, and found that this drug suppresses relapse to compulsive food seeking in a rat model. In humans, such relapse is a major problem during diet treatment and is often induced by stress or anxiety states. These and other data suggest that CRH is involved in stress-induced relapse to palatable food seeking and that CRH1 antagonists should be considered for the treatment of maladaptive eating habits. In our opioid program, we found delta opioid receptor mediated antidepressant-like activity in the delta opioid agonists SNC-80 and SNC-86 [(+)-BW373U86] suggesting possible therapeutic utility of drugs with this profile. We further showed that SNC-86 upreguated brain neurotrophic factor mRNA and its high-affinity tyrosine kinase receptor in the frontal cortex and hippocampus of rats like the classical antidepressants desipramine and buproprion. Unlike classical antidepressants however, SNC-86 showed its effect acutely via delta receptors suggesting that delta opioid receptor agonists could be good targets for faster acting antidepressants via a novel mechanism. Finally, we showed that tolerance to the antidepressant effects of SNC-80 did not develop indicating that delta-opioid agonists could be effective on a long-term basis for antidepressant therapy. The treatment and prevention of abuse of the psychomotor stimulants cocaine and methamphetamine are critical areas from a health and societal viewpoint. Earlier, we showed that our lead compound GBR12909 nearly eliminated cocaine self-administration in the rhesus monkey at doses that had no effect on feeding behavior, the standard measure of normal behavior. We also synthesized the decanoate ester of a racemic hydroxy GBR12909 derivative that largely suppressed cocaine self-administration for nearly a month with only one dose. We studied four other related compounds and all showed the ability to suppress cocaine self-administration without affecting food intake in the rhesus monkey. These four compounds are potential candidates for clinical trials that and can be converted to ultra long-acting prodrugs. These drugs exert these effects through inhibition of biogenic amine reuptake. We have now synthesized a broad array of drugs in this program with a range of binding and reuptake inhibition selectivity for dopamine, serotonin and norepinepherine transporters. We have continued to study them and found that some of these compounds have low to subnanomolar binding affinity and single digit nanomolar reuptake inhibition. Finally, we published reviews on the following topics: (a) neurochemical normalization therapeutics for stimulant abuse, (b) new tools to monitor stress using PET imaging and (c) CRH receptor type 1 antagonists and their applications in psychosomatic disorders. 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.