Cocaine analgesia: An in vivo structure-activity study

Hot plate testing of rats was performed to determine the optimal analgesic doses of intracerebroventricularly (ICV) administered cocaine, significant cocaine metabolites, and selected structurally similar molecules. Optimal, (subseizure) analgesic doses for cocaine and selected cocaine analogues were (in mu M): cocaine, 0.37; cocaethylene, 0.09; benzoylecgonine, 0.35; norcocaine, 0.43; and ecgonine, 2.1. Ecgonine methyl ester was not analgesic at less than or equal to 3.7 pM. These results, in conjunction with findings on other structurally similar molecules suggest that, of the molecules tested, (a) a hydrophobic group at the C-3 attached carbon is critical for analgesia; (b) a hydrophobic C-2 ester group can enhance analgesic activity (e.g., cocaethylene); (c) the N-methyl position is minimally important for analgesia; and (d) isomeric configurational changes can influence analgesia.