Dextrorphan, (+)3-hydroxy-N-methyl-morphinan, is a selective noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) class of excitatory amino acid receptors. Dextrorphan is the O-demethylated primary metabolite of the over-the-counter antitussive dextromethorphan. Dextromethorphan abuse has been documented in various countries over the last 30 years, whereas outbreaks of dextromethorphan abuse by teenagers has surfaced as a social problem recently in several cities in the U.S. The euphoriant and hallucinogenic effects of dextromethorphan and dextrorphan are similar to those of phencyclidine (PCP) and, in an analogous manner, derive from the ability of these compounds to act as antagonists of the NMDA receptor. Dextrorphan is however more potent than dextromethorphan as a NMDA receptor antagonist. Notwithstanding the commonalities of action between dextrorphan and prototypic noncompetitive NMDA antagonists such as PCP and MK-801, dextrorphan blockade of NMDA receptors has been distinguished by distinct kinetics, use-dependency and subtype selectivity. This research program is directed toward a quantitative mechanistic description of dextrorphan binding to and antagonism of the NMDA receptor ion-channel and NMDA receptor ion-channel antagonism. The central hypothesis to be evaluated is that the binding domain within the NMDA receptor ion channel recognized by dextrorphan is distinct and therefore nonidentical to the site labeled by MK-801. An interaction with distinct, yet proximate, binding domains by dextrorphan and MK-801 is posited to underlie the distinguishing pharmacological actions of these two compounds. This proposal attempts to combine kinetic analysis of ligand binding and channel antagonism with molecular biological approaches to determine the sites of interaction for dextrorphan and MK-801 in the NMDA receptor ion channel. The use of recombinant NMDA receptors will permit delineation of the molecular basis for the distinct regional and pharmacological profiles of [3/H]MK-801 and [3/H]dextrorphan labeling of NMDA receptors in rat brain. A mechanistic description of the distinctive NMDA receptor antagonism produced by dextrorphan, MK-801 and PCP analogs, will provide a further understanding of the differing propensities of these compounds to produce psychotomimetic effects.
| 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 |
