Novel anticonvulsant analogs of dextromethorphan: improved efficacy, potency, duration and side-effect profile.
The anticonvulsant and neuroprotective activity of dextromethorphan (DM, [+]-3-methyl-17-methylmorphinan) may be, in part, due to its metabolism to the phencyclidine hydrochloride-like compound dextrorphan (DX). We evaluated the anticonvulsant activity and neurological impairing effects in rats of three novel analogs of DM which, based upon their position-3 substituents, would either not be expected to be metabolized to DX or might do so at a reduced rate. The DM analogs were determined to be more potent and more efficacious than DM against maximal electroshock convulsions; two of the analogs, namely [(+)-3-ethoxy-17-methylmorphinan] and [(+)-3-(2-propoxy)-17-methyl-morphinan], were equipotent to DX. [(+)-3-(Ethoxy-17-methylmorphinan], and [(+)-3-(2-propoxy)-17-methylmorphinan) exhibited a duration of action (1-2 hr) slightly longer than DX (0.5-1 hr) and similar to DM (2-4 hr). The anticonvulsant effect of [(+)-3-amino-17-methylmorphinan] persisted 4-6 hr. Against flurothyl convulsions DM was proconvulsant, DX was anticonvulsant and the DM analogs were inactive. In contrast, N-methyl-D-aspartate convulsions were antagonized by i.c.v. pretreatment with DM and the DM analogs, albeit with a potency approximately 10 times less than that of DX. Results of rotarod performance testing further distinguished the analogs from DM, DX or the anticonvulsant drug diazepam. No behavioral impairment was observed at the highest doses tested of each of the DM analogs, resulting in protective indices (i.e., rotarod TD50/maximal electroshock anticonvulsant ED50) greatly exceeding DM, DX or clinical anticonvulsant drugs. The results of this study establish these 3-substituted DM analogs as novel anticonvulsants exhibiting improved potency, efficacy, duration and side-effect profiles.
Tortella
F C
FC
Department of Medical Neurosciences, Walter Reed Army Institute of Research, Washington, District of Columbia.
Robles
L
L
Witkin
J M
JM
Newman
A H
AH
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003915:Dextromethorphan / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000927:Anticonvulsants; D016202:N-Methylaspartate; D003915:Dextromethorphan