Alice Sebastian

14β-Chlorocinnamoylamino derivatives of metopon: long-term μ-opioid receptor antagonists

The affinity, selectivity and antinociceptive properties of 5β-methyl-14β-(p-chlorocinnamoylamino)-7,8-dihydromorphinone (MET-Cl-CAMO) and N-cyclopropyl-methyl-5β-methyl-14β-(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 IC50 values of less than 2 nM. Preincubation of membranes with MET-Cl-CAMO and N-CPM-MET-Cl-CAMO produced a concentration-dependent, wash-resistant inhibition of μ-opioid receptor binding. Saturation binding experiments with N-CPM-MET-Cl-CAMO showed a reduction in the number of μ-opioid binding sites without a change in affinity. In the mouse 55°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 δ- or κ-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, μ-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 μ-opioid receptor.

Suppression of morphine and cocaine self-administration in rats by a mixed mu antagonist-kappa agonist (N-CBM-TAMO) and a long-acting selective D1 antagonist (AS-300)

Abstract N-CBM-TAMO 2 was prepared by the same procedure as used for TAMO 1 . It was found to be a short-term kappa agonist and a long-term mu antagonist. The benzazepine 12 , (AS-300) was a potent selective D 1 antagonist. Both compounds suppressed cocaine and morphine self-administration in rats at doses which did not affect water consumption. The synthesis of N-CBM-TAMO ( 2 ) and AS-300 ( 12 ) is described. Both drugs block cocaine and morphine self-administration in rats.

Metopon and two unique derivatives: Affinity and selectivity for the multiple opioid receptors

5 beta-Methyl-7,8-dihydromorphinone (metopon), an isomer [6aS-(6a alpha,9a alpha, 10 beta)13aS]-1,10-methano-4-hydroxy-11-methyl- 6,6a,8,9,10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]isoquinoline- 7-(9aH)-one (compound 1) derived from a photochemical rearrangement of 5 beta-methylmorphinone, and [6aS-(6a alpha,9a alpha,10 beta)13aS]-1,10-methano-4-hydroxy-11-methyl- 6,6a,8,9, 10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]-14 beta- (p-nitrocinnamoylamino) isoquinoline-7-(9aH)-one (compound 2) were characterized for opioid receptor affinity, selectivity and analgesic properties. In competition binding assays using bovine striatal membranes, the three compounds inhibited the binding of 0.25 nM [3H][D-Ala2,(Me)-Phe4,Gly(ol)5]enkephalin (DAMGO), a mu-selective peptide, with IC50 values less than 5 nM. All three compounds exhibited lower affinity for delta- and kappa-opioid receptors. In the mouse 55 degrees C warm-water tail-flick assay, both metopon and compound 1 displayed antinociception that lasted for 60 min after i.c.v. injection. Morphine sulfate, metopon and compound 1 produced 50% antinociception with i.c.v. doses of 0.83, 2.0 and 4.0 nmol, respectively. The mu-selective, irreversible opioid receptor antagonist beta-funaltrexamine blocked antinociception induced by metopon and compound 1, while delta- and kappa-opioid receptor selective antagonists did not effect antinociception. These findings demonstrate metopon and its isomer bound with high affinity to the mu-opioid receptor and produced antinociception through this receptor.

5β-Methyl-14β-(p-nitrocinnamoylamino)-7,8-dihydromorphinone: A long-lasting μ-opioid receptor antagonist devoid of agonist properties

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone (MET-CAMO) suppressed morphine-induced antinociception but had no effect on antinociception mediated by delta- or kappa-opioid receptors after a single i.c.v. 1-nmol injection from 8 to 72 h before testing. MET-CAMO had no agonist effects in the mouse tail-flick assay in doses up to 100 nmol. MET-CAMO is the first N-methylated morphine derivative which shows such long-lasting mu-selective opioid receptor antagonism with no agonistic properties.

N-Methyl and N-cyclopropylmethyl-14α,14′β-[dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis(7,8-dihydro-5β-methyl-morphinone) MET-TAMO and N-CPM-MET-TAMO: Synthesis and opioid binding properties

Abstract MET-TAMO and N-CPM-MET-TAMO were prepared by the same procedure used for the corresponding 5-desmethyl compounds, TAMO and N-CPM-TAMO, except that a new procedure was employed to synthesize the intermediate, 14β-amino-7,8-dihydromorphinone. Both MET-TAMO and N-CPM-MET-TAMO produced wash-resistant inhibition of μ, δ and κ binding but were more potent at the μ receptor.