Mixed κ/μ partial opioid agonists as potential treatments for cocaine dependence.

Cocaine use activates the dopamine reward pathway, leading to the reinforcing effects of dopamine. There is no FDA-approved medication for treating cocaine dependence. Opioid agonists and antagonists have been approved for treating opioid and alcohol dependence. Agonists that activate the μ opioid receptor increase dopamine levels in the nucleus accumbens, while μ receptor antagonists decrease dopamine levels by blocking the effects of endogenous opioid peptides. Activation of the κ opioid receptor decreases dopamine levels and leads to dysphoria. In contrast, inhibition of the κ opioid receptor decreases dopamine levels in the nucleus accumbens. Antagonists acting at the κ receptor reduce stress-mediated behaviors and anxiety. Mixed partial μ/κ agonists have the potential of striking a balance between dopamine levels and attenuating relapse to cocaine. The pharmacological properties of mixed μ/κ opioid receptor agonists will be discussed and results from clinical and preclinical studies will be presented. Results from studies with some of the classical benzomorphans and morphinans will be presented as they lay the foundation for structure-activity relationships. Recent results with other partial opioid agonists, including buprenorphine derivatives and the mixed μ/κ peptide CJ-15,208, will be discussed. The behavioral effects of the mixed μ/κ MCL-741, an aminothiazolomorphinan, in attenuating cocaine-induced locomotor activity will be presented. While not a mixed μ/κ opioid, results obtained with GSK1521498, a μ receptor inverse agonist, will be discussed. Preclinical strategies and successes will lay the groundwork for the further development of mixed μ/κ opioid receptor agonists to treat cocaine dependence.