Dextrorphan is the major metabolite dextromethorphan a clinically used over-the-counter antitussive. Dextrorphan and related dextrorotatory morphinans and benzomorphans are similar to the dissociative anesthetics phencyclidine (PCP) and ketamine in that they act as selective noncompetitive antagonists of the NMDA receptor. This relationship has been established at the electrophysiological level where dextrorphan has been shown, like PCP and ketamine, to be a potent antagonist of NMDA- induced excitation in spinal cord neurons. At the behavioral level dextrorphan shares discriminative stimulus properties with PCP suggesting a common basis of action for these two compounds. Notwithstanding the commonalities of action between dextrorphan and other noncompetitive antagonists of NMDA receptors, the results of both radioligand binding and electrophysiological experiments suggest that the mechanism of dextrorphan interaction with the PCP recognition domain of the NMDA receptor is distinctive. Dextrorphan is unique in that it does not exhibit the striking use-dependence that is characteristic of the NMDA receptor blockade produced by PCP, ketamine and MK-801. The focus of the proposed project is to elucidate the molecular mechanisms which underlie the unique actions of dextrorphan. These studies will utilize [3H]dextrorphan as a probe for PCP receptors. Investigation of association and dissociation kinetics will be performed to delineate the mechanism of [3H]dextrorphan binding to the PCP receptor in rat brain membranes. The distribution and pharmacological signature of [3H]dextrorphan binding sites will be determined in brain slices using quantitative receptor autoradiography. To explore correlations between the potencies as anticonvulsants, the ability of these ligands to suppress seizures evoked by kainic acid in the rat prepiriform cortex will be evaluated. These results will establish the functional consequences of ligand interaction with the dextrorphan binding site in a region of the cerebral cortex. The potential for anatomically distinct forms of the labeled receptor will be assessed through the investigation of biochemical and physiological regulation of the receptor. A further characterization of dextrorphan as a probe for the PCP receptor may provide useful insights into the therapy of epilepsy, schizophrenia, ischemic cell death and drug abuse.
| Nunnery, Joshawna K; Engene, Niclas; Byrum, Tara et al. (2012) Biosynthetically intriguing chlorinated lipophilic metabolites from geographically distant tropical marine cyanobacteria. J Org Chem 77:4198-208 |
