DEXTROROTATORY OPIOIDS AS PROBES FOR PCP RECEPTORS

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date7/15/923/31/01

Funding

  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse

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