Attenuation of the stimulant and convulsant effects of cocaine by 17-substituted-3-hydroxy and 3-alkoxy derivatives of dextromethorphan.

Pharmacological evidence has suggested a role for both sigma and N-methyl-D-aspartate (NMDA) receptors in the behavioral stimulant effects of cocaine and its convulsant effects observed at higher doses. A series of dextromethorphan (DM) analogs with a range of affinities for sigma-1 binding sites and for the NMDA receptor ion channel were used to explore the contribution of these two mechanisms in controlling the stimulant and convulsant effects of cocaine. These compounds were potent and efficacious blockers of both stimulant and convulsant effects produced by acute cocaine administration in mice (cocaine 10 or 75 mg/kg ip for locomotor activity or convulsions, respectively). Generally, the DM analogs blocked these effects of cocaine at doses that did not display ataxic and sedative side effects as measured in the inverted screen test. In contrast to the high-affinity NMDA blockers, (+)-MK-801 (dizocilpine) and dextrorphan (DX), DM and analogs did not stimulate locomotor activity. There was no significant correlation between the affinities of the DM analogs for the sigma-1 or the phencyclidine (PCP) binding site and their potencies to produce behavioral effects on their own or to attenuate the behavioral or toxic effects of cocaine. The present study has identified a series of agents that have cocaine-blocking effects that appear to be distinct from that of classical sigma-1 receptor ligands and that of traditional uncompetitive NMDA receptor antagonists. These findings point to potentially novel pharmacological strategies for blocking cocaine stimulant and toxic effects.