Samidorphan (INN, USAN) (developmental code names ALKS-33, RDC-0313), also known as 3-carboxamido-4-hydroxynaltrexone, is an opioid antagonist that preferentially acts as an antagonist of the μ-opioid receptor (MOR). It is under development by Alkermes for the treatment of major depressive disorder and possibly other psychiatric conditions.
|Synonyms||ALKS-33, RDC-0313; 3-Carboxamido-4-hydroxynaltrexone|
|Elimination half-life||7–9 hours|
|Chemical and physical data|
|Molar mass||370.441 g/mol g·mol−1|
|3D model (JSmol)|
Samidorphan has been investigated for the treatment of alcoholism and cocaine addiction by its developer, Alkermes, showing similar efficacy to naltrexone but possibly with reduced side effects.
However, it has attracted much more attention as part of the combination product ALKS-5461 (buprenorphine/samidorphan), where samidorphan is combined with the mixed MOR weak partial agonist and κ-opioid receptor (KOR) antagonist buprenorphine, as an antidepressant. Buprenorphine has shown antidepressant effects in some human studies, thought to be because of its antagonist effects at the KOR, but has not been further developed for this application because of its MOR agonist effects and consequent abuse potential. By combining buprenorphine with samidorphan to block the MOR agonist effects, the combination acts more like a selective KOR antagonist, and produces only antidepressant effects, without typical MOR effects such as euphoria or substance dependence being evident.
Samidorphan is also being studied in combination with olanzapine, as ALKS-3831 (olanzapine/samidorphan), for use in schizophrenia. It is hoped it will be effective while resulting in less weight gain. Phase II studies have begun.
- μ-Opioid receptor (Ki = 0.052 nM; EC50 = N/A; Emax = 3.8%; IC50 = 0.88 nM; Imax = 92%)
- κ-Opioid receptor (Ki = 0.23 nM; EC50 = 3.3 nM; Emax = 36%; IC50 = 38 nM; Imax = 57%)
- δ-Opioid receptor (Ki = 2.6 nM; EC50 = 1.5 nM; Emax = 35%; IC50 = 6.9 nM; Imax = 56%)
As such, samidorphan is primarily an antagonist or extremely weak, like almost comically weak partial agonist of the MOR, and also acts, to a lesser extent, as a weak partial agonist of the KOR and as a weak partial agonist of the DOR. In accordance with its in vitro profile, samidorphan has been observed to produce some side effects that are potentially consistent with activation of the KOR such as somnolence, sedation, dizziness, and hallucinations in some patients in clinical trials at the doses tested.
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- Investigational ALKS 5461 Channels ‘Opium Cure’ for Depression
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