14 beta-Chlorocinnamoylamino derivatives of metopon: long-term mu-opioid receptor antagonists.
The affinity, selectivity and antinociceptive properties of 5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7,8-dihydromorphinone (MET-Cl-CAMO) and N-cyclopropyl-methyl-5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7, 8-dihydronormorphinone (N-CPM-MET-Cl-CAMO) for the multiple opioid receptors were characterized. In competition binding assays using bovine striatal membranes, both compounds inhibited the binding of 0.25 nM [3H][D-Ala2, (Me)-Phe4,Gly(ol)5]enkephalin (DAMGO) with IC 50 values of less than 2 nM. Preincubation of membranes with MET-CI-CAMO and N-CPM-MET-Cl-CAMO produced a concentration-dependent, wash-resistant inhibition of mu-opioid receptor binding. Saturation binding experiments with N-CPM-MET-Cl-CAMO showed a reduction in the number of mu-opioid binding sites without a change in affinity. In the mouse 55 degrees C warm-water tail-flick assay, neither MET-Cl-CAMO nor N-CPM-MET-Cl-CAMO at doses up to 100 nmol produced antinociception after intracerebroventricular administration, but morphine-induced antinociception was antagonized in a time- and dose-dependent manner by both compounds. The antagonism produced by 1 nmol of either MET-Cl-CAMO or N-CPM-MET-Cl-CAMO reached a maximal effect after 24 h, and lasted up to 48 h. Analgesia mediated by delta- or kappa-opioids was not altered by either compound. In summary, the data suggest that MET-Cl-CAMO and N-CPM-MET-Cl-CAMO are long-term, mu-opioid receptor antagonists, devoid of agonist properties in the mouse tail-flick assay, and that N-CPM-MET-Cl-CAMO may produce its antagonistic effects by binding irreversibly to the mu-opioid receptor.
McLaughlin
J P
JP
Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, NY 14642-8711, USA.
Sebastian
A
A
Archer
S
S
Bidlack
J M
JM
D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides; D001667:Binding, Competitive; D002417:Cattle; D003342:Corpus Striatum / Q000378:metabolism / Q000648:ultrastructure; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000378:metabolism / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014316:Tritium
C106523:5-methyl-14-(4-chlorocinnamoylamino)-7,8-dihydromorphinone; D000700:Analgesics; D044482:Benzeneacetamides; D004745:Enkephalins; D009019:Morphinans; C106524:N-cyclopropylmethyl-5-methyl-14-(4-chlorocinnamoylamino)-7,8-dihydronormorphinone; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017450:Receptors, Opioid, mu; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; C045444:U 69593