14-BETA-CHLOROCINNAMOYLAMINO DERIVATIVES OF METOPON - LONG-TERM MU-OPIOID RECEPTOR ANTAGONISTS

The affinity, selectivity and antinociceptive properties of 5 beta-met hyl-14 eta-(p-chlorocinnamoylamino)-7,8-dihydromorphinone (MET-Cl-CAMO ) and N-cyclopropyl-methyl-5 beta-methyl-14 -(p-chlorocinnamoylamino)- 7,8-dihydronormorphinone (N-CPM-MET-Cl-CAMO) for the multiple opioid r eceptors were characterized. In competition binding assays using bovin e striatal membranes, both compounds inhibited the binding of 0.25 nM [H-3][D-Ala(2),(Me)-Phe(4), Gly(ol)(5)]enkephalin (DAMGO) with IC50 va lues of less than 2 nM. Preincubation of membranes with MET-Cl-CAMO an d N-CPM-MET-Cl-CAMO produced a concentration-dependent, wash-resistant inhibition of mu-opioid receptor binding. Saturation binding experime nts with N-CPM-MET-Cl-CAMO showed a reduction in the number of mu-opio id 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-C AMO at doses up to 100 nmol produced antinociception after intracerebr oventricular administration, but morphine-induced antinociception was antagonized in a time- and dose-dependent manner by both compounds. Th e 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. Analg esia mediated by delta- or kappa-opioids was not altered by either com pound. 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 m ay produce its antagonistic effects by binding irreversibly to the mu- opioid receptor.