Treatment of schizophrenia and psychostimulant dependence/abuse is highly costly. These conditions are often comorbid and lack effective pharmaceutic treatments. Both typical and atypical schizophrenic medications like Abilify and Haldol work by functioning as dopamine D2 receptor antagonists. A major side effect of D2 antagonists is tardive dyskinesia. There are no FDA-approved medications for the substance abuse of methamphetamine or cocaine. Rimonabant is a cannabinoid type 1 receptor inverse agonist that was used as an anorectic antiobesity drug but was recalled due to psychiatric side effects relating to suicidal ideation. CB1 cannabinoid type 1 receptor antagonists have been shown to block cocaine reinstatement in rats. Because both dopamine and cannabinoid receptors are involved in the mesolimbic system, we hypothesized that agents targeting these receptors in a new way may prove beneficial in combating schizophrenia and substance abuse. First, antagonism of the D2-like D4 receptor should be similarly effective at treating schizophrenia without causing dyskinesia; second, CB1R negative allosteric modulators may block the rewarding effects of stimulants without causing the same anhedonic effects. Previous work in the Cunningham laboratory has identified two compounds that are believed to be the first dual-acting blockers of these preferred receptors. However, both compounds have a higher binding affinity for D4R than CB1R receptors. The major goal of this research was to discover and synthesize analog compounds with more balanced affinity for these two receptors.
