CVL-936 is a selective dopamine D3-preferring, D2/D3 receptor subtype antagonist that we are developing for the treatment of substance use disorder (SUD).
About the Mechanism of CVL-936
Though specific causal links to addictive behavior in humans are not fully understood, excessive signaling via D3 receptors may contribute to intense reward-seeking behavior. Commonly abused drugs have been shown to increase dopamine levels in the nucleus accumbens, where the D3 receptor is preferentially expressed, and postmortem studies have shown D3 mRNA levels were increased six-fold in the nucleus accumbens of cocaine-overdose fatalities compared to age-matched control subjects. Based on this evidence, together with other clinical data and preclinical activity of D3-preferring antagonists, including CVL-936, in relevant preclinical models, the D3 receptor appears to be central in the neurobiology of drug abuse, and we believe D3-preferring antagonists could have therapeutic value for the treatment of addiction.
CVL-936 was designed to selectively block the binding of dopamine to D3 receptors on neurons located in the brain’s reward circuits, while reducing, but not fully inhibiting, signaling at D2 receptors. This ratio of D3/D2 inhibition may help re-balance the dysregulation that takes place in the reward pathway during relapse from substance addiction. Additionally, CVL-936, because it binds preferentially to D3 over D2 receptor subtypes, has the potential to minimize D2-induced side effects such as sedation and acute withdrawal. With this approach, CVL-936 may help normalize the assessment of reward and consequences of behavior, preventing further relapse.