Drug misuse, abuse, and addiction are major health concerns, and cocaine is one of the most widely abused illegal drugs. Despite widespread understanding in the medical and research communities that addiction results in physiological changes in the brain, there is currently no FDA-approved pharmacological treatment for cocaine addiction, making this an important unmet medical need. The role of the opioid system in regulating the rewarding properties of drugs of abuse demonstrates potential for opioids to be used in the treatment of addiction. Specifically, it has been demonstrated that KOR (kappa opioid receptor) agonists have the potential to reduce cocaine self-administration in non-human primates. However, KOR activation is associated with negative side effects such as dysphoria which limit the clinical utility of these ligands. It has been suggested that partial MOR (mu opioid receptor) agonism may be able to mitigate dysphoria associated with KOR agonism, increasing the therapeutic potential of a KOR agonist. We report a series of novel MOR partial agonist/KOR agonist ligands based on the dimethyltyrosine-tetrahydroisoquinoline (DMT-Tiq) scaffold. Installation of a 7-benzyl pendant on the tetrahydroisoquinoline aromatic ring introduced strong KOR agonism. A series of small modifications led to the development of several structurally similar MOR partial agonist/KOR agonist compounds with slightly different pharmacological profiles.

Design and synthesis of novel opioid peptidomimetics for potential treatment of cocaine addiction

256th National Meeting (2018)

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