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Samidorphan is a novel opioid-system modulator, similar to naltrexone, that functions primarily as a μ-opioid receptor antagonist in vivo and is used primarily in combination with antipsychotics to reduce their metabolic dysfunction-associated adverse effects.
Samidorphan is a novel opioid-system modulator, similar to naltrexone, that functions primarily as a μ-opioid receptor antagonist in vivo and is used primarily in combination with antipsychotics to reduce their metabolic dysfunction-associated adverse effects.
Samidorphan is a novel naltrexone analogue containing a 3-carboxamido group that functions as an opioid receptor modulator, both in vitro and in vivo. Numerous in vitro studies have demonstrated that samidorphan binds with high affinity to the μ-, κ-, and δ-opioid receptors with K values of 0.052 ± 0.0044, 0.23 ± 0.018, and 2.7 ± 0.36 nM, respectively. Samidorphan acts as an antagonist at the μ-opioid receptor when it signals through G proteins, a partial agonist when the receptor signals through G, G, and G proteins, and essentially lacks β-arrestin-mediated signalling; samidorphan also acts as a partial agonist at both the κ- and δ-opioid receptors in vitro. In addition, both the major N-dealkylated and the major N-oxide human metabolites bind to the μ-, κ-, and δ-opioid receptors (K values of 0.26, 23, and 56, and 8, 110, and 280 nM, respectively); the former functions as a μ-opioid receptor agonist and the latter as an antagonist. Overall, samidorphan functions primarily as a μ-opioid antagonist in vivo. Olanzapine is an efficacious antipsychotic whose use is limited, in part, by known adverse effects mediated through metabolic dysfunction: hyperglycemia/diabetes mellitus, hyperlipidemia, and weight gain. The exact mechanisms behind this metabolic dysfunction are incompletely understood, but it is known that opioid signalling is involved in feeding and metabolism. Clinical studies have demonstrated that the addition of samidorphan to olanzapine helps mitigate its metabolic-related adverse effects; presumably, this is due to opioid receptor signalling, though the exact mechanism remains to be determined. The appropriateness of samidorphan in combination therapy is due in part to its relatively mild side effect profile and low abuse potential.
Samidorphan is indicated in combination with olanzapine for the treatment of bipolar I disorder, either as an adjunct to lithium or valproate or as monotherapy for the acute treatment of manic or mixed episodes or as maintenance therapy, and for the treatment of schizophrenia in adults.
