Dextromethorphan Analogs: Receptor Binding and Pharmacological Profile of Novel Anticonvulsant/Neuroprotectant Drugs
Abstract
A series of 3-substituted 17-methylmorphinan analogs of dextromethorphan (DM) have been developed which are anticonvulsant against maximal electroshock seizures in rats. These findings have been extended to a rat model of NMDA convulsions where it has been determined that the aniline (AHN649), O-ethylether (AHN1036) and 0-isopropylether (AHN1037) analogs are anticonvulsant. Recent assessments of neurologic impairment have shown that these DM analogs also display exceptional side-effect profiles, yielding protective indices several fold greater than those established for other standard anticonvulsant drugs. In in vitro and in vivo models of neuronal injury we have determined that AHN649 is at least equipotent to DM as a neuroprotectant. Finally, analysis of binding potencies has revealed no appreciable activity at the non-competitive PCP/MK801 site or the glycine modulatory site of the NMDA receptor complex. Alternatively, interactions with distinct high affinity DM binding sites in brain appear to be involved. We propose that these potent, safe analogs of DM may be of potential therapeutic utility as adjuncts in the treatment of agent-induced convulsions and neurotoxicity.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 13, 1993
- Accession Number
- ADP008801
Entities
People
- B. Davis
- F. C. Tortella
- J. M. Witkin
- L. Robles
- M. A. Decoster
Organizations
- Walter Reed Army Institute of Research