A Novel Maintenance Therapeutic for Opioid Use Disorder

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 378; no. 2; pp. 133 - 145
• Main Authors: Youngblood, Beth, Li, Kevin, Gehlert, Donald R, Medina, Julio C, Schwartz, Neil
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2021; American Society for Biochemistry and Molecular Biology
• Subjects: Analgesics, Opioid - pharmacology; Analgesics, Opioid - therapeutic use; Animals; Buprenorphine - pharmacology; Buprenorphine - therapeutic use; Drug Discovery and Translational Medicine; Humans; Naltrexone - pharmacology; Naltrexone - therapeutic use; Narcotic Antagonists - pharmacology; Narcotic Antagonists - therapeutic use; Opiate Substitution Treatment - methods; Opioid-Related Disorders - drug therapy; Receptors, Opioid, mu - agonists; Substance Withdrawal Syndrome - drug therapy; MOR; SD; CPP; FDA; GTPγS; MPE; HCVR; CNS; 95% CI; mean diff; OUD
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.120.000214

Opioid use disorder (OUD) is a major socioeconomic burden. An ideal OUD pharmacotherapy will mitigate the suffering associated with opioid-withdrawal, inhibit the effects of high efficacy opioids, and minimize opioid-cravings while being safe and accessible to a diverse patient population. Although current OUD pharmacotherapies inhibit the euphoric effects of opioids of abuse, the extent to which they safely alleviate withdrawal and opioid-cravings corresponds with their intrinsic µ opioid receptor (MOR) efficacy. In addition to inhibiting the euphoric effects of opioids of abuse, the medium efficacy MOR agonist buprenorphine alleviates withdrawal and opioid-cravings, but its intrinsic MOR efficacy is sufficient such that its utility is limited by abuse and safety liabilities. Although the MOR antagonist naltrexone minimizes euphoria and has no abuse liability, it exacerbates suffering associated with withdrawal and opioid cravings. Therefore, a therapeutic with intrinsic MOR activity between the partial agonist (buprenorphine) and the antagonist (naltrexone) would strike a balance between the benefits and liabilities of these two therapeutics. To address this need, we derived RM1490, an MOR agonist based on a nonmorphinan scaffold that exhibits approximately half the intrinsic MOR efficacy of buprenorphine. In a series of preclinical assays, we compared RM1490 with buprenorphine and naltrexone at doses that achieve therapeutic levels of central nervous system MOR occupancy. RM1490 exhibited a behavioral profile consistent with reduced reward, dependence, and precipitated withdrawal liabilities. RM1490 was also more effective than buprenorphine at reversing the respiratory depressant effects of fentanyl and did not suppress respiration when combined with diazepam. In preclinical studies, RM1490 has a physiological and behavioral profile suitable for opioid use disorder maintenance therapy.