Archer: Evaluation of THlP in standard tests for analgesic activity: Occurrence of antinociception and hyperalgesia. Drug Dev. Res. 4:405-419, 1984. THlP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), a structurally rigid analog of the GABAagonist muscimol, was investigated for antinociceptive activity in a variety of preclinical tests for analgesic activity. Antinociceptive activity was observed in the mouse writhing, mouse hot plate, rat tail flick, rat inflamed paw, and monkey shock titration tests. In the mouse writhing, mouse hot plate, and rat tail jerk experiments, periods of significant hyperalgesia were noted either prior to or following the occurrence of THIP-induced antinociception. At those times when an antinociceptive effect of THlP could be demonstrated in the test systems employed in this study, a variety of unfavorable effects were noted including sedation, ataxia, myoclonic jerks, and vomiting. These side-effects of THlP first appeared near the dose that produced antinociception in 50% of the animals (EDs0 value) and became progressively more intense as the dose increased. Neither the narcotic antagonist naloxone, the cholinergic antagonist atropine, nor the GABA-antagonists bicuculline or picrotoxin blocked the antinociceptive activity of THIP. The synthesis of prostaglandins was not inhibited by THIP. The antinociceptive activity of THlP is an interesting lead in the search for a novel analgesic that lacks the undesirable effects of opiates. However, the occurrence of hyperalgesia and marked side-effects at doses near the effective analgesic dose may limit THIP's therapeutic potential.
Leander, J.D., and D.M. Zimmerman: Antagonism of bremazocine-induced urination as a test for kappa-opioid receptor antagonists within the phenylpiperidine series. Drug Dev. Res. 4:421-427, 1984.Representative compounds from a series of phenylpiperidine-opioid antagonists were compared in their ability to antagonize the diuretic effect of 0.08 mglkg of bremazocine, a kappa-opioid receptor agonist. Three of the compounds produced dose-related antagonism of bremazocine, whereas four others did nor. The four ineffective compounds also did not exhibit any kappa agonist activity. The potency of the three effective antagonists did not correlate with their antagonist activity against morphine or in suppressing deprivation-induced drinking. These results demonstrate that several kappa receptor antagonists can be found in the phenylpiperidine series of opioid antagonists, and further emphasize the usefulness of kappa-mediated diuresis as an in vivo test for kappa-opioid receptor activity.
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