Neural Responses to Injury: Prevention, Protection, and Repair. Volume 5. Neuropharmacology of Delta Receptor Agonists and Antagonists

摘要

Studies in the Division of Neuropharmacology investigated the role of endogenous opioid systems in learning and memory, ventilatory function and antinociception. The goal of these studies was: to identify and characterize candidate ligands that might be useful in studies on delta opioid mechanisms; and to use these compounds to systematically investigate the role of delta systems in complex behavioral processes, in respiration and in the perception of noxious stimuli. The first candidate compound was BW373U86, which is a highly- selective agonist for the delta opioid receptor. BW373U86 had effects that differed from those of other prototypic opioid agonists. BW373U86 failed to produce antinociceptive effects in rhesus monkeys. Although BW373U86 had effects that were unique from the effects obtained with prototypic mu or kappa opioid agonists, the behavioral and pharmacological profile for this agonist was disappointing. A second candidate compound which was focused upon was OHM3507. This compound differs from morphine in that it does not suppress the immune system. It was hypothesized that this differences might be due to activity at the delta opioid receptor. The pharmacologic and behavioral effects of the fentanyl derivative OHM35O7 were assessed to determine if this compound had increased antinociceptive effects and a reduced number of undesirable effects (e.g., respiratory depression) as compared to the prototypic opioids (e.g., fentanyl, morphine). Studies were undertaken to determine the opioid receptor selectivity of OHM3507 using behavioral assays in rhesus monkey.