| Abstract: |
14-Methoxymetopon (4,5alpha-epoxy-3-hydroxy-14beta-methoxy-5beta,17-dimethylmorphinan-6-on e)is a selective mu opioid receptor agonist. In animal models, it is far more potent than morphine and is associated with decreased tolerance, lower physical dependence and far less respiratory depression. (3H)14-methoxymetopon binding in rat brain is saturable with a high affinity and selectivity for the mu opioid receptor. The current study has examined its binding in both calf brain membrane and Chinese hamster ovary cells (CHO) stably transfected with splice variants of the mouse mu opioid receptor gene (MOR-1). (3H)14-methoxymetopon binding in striatum reaches equilibrium levels within 150 minutes at 25degree C. Highest binding levels were observed in the striatum, followed by the periaqueductal gray, cerebellum, thalamus, frontal cortex, and brain stem. Dissociation studies are consistent with a single population of sites. Binding is enhanced by divalent cations and reduced by sodium chloride and guanine nucleotides, consistent with agonist binding. Saturation studies reveal that (3H)14-methoxymetopon has a higher affinity (KD = 0.264nM) than either the agonist (3H)DAMGO (KD = 0.613 nM) or the antagonist (3H)naloxone (KD = 1.712nM). However, the Bmax for (3H)14-methoxymetopon was approximately the same as (3H)naloxone and almost twice that of (3H)DAMGO. Delta and kappa agonists compete with much lower affinity, confirming its mu selectivity. (3H)14-methoxymetopon also labels the MOR-1 splice variants with high affinity. |
