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The dopamine stabilizers ACR16 and (−)-OSU6162 display nanomolar affinities at the σ-1 receptor

Molecular Psychiatry volume 18, pages 12–14 (2013)Cite this article

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Converging in vivo evidence has advanced the σ-1 receptor as a pharmacological target for the treatment of neurological and psychiatric disorders such as L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, schizophrenia, drug addiction and depression (see reviews refs 1,2). Considering their close structural resemblance to known σ-1 receptor ligands,3 we investigated the ability of dopaminergic stabilizers, a new class of phenylpiperidine compounds, to bind to σ-1 receptors.

Dopaminergic stabilizers are presently being investigated for use in neurological and psychiatric disorders.4, 5 These agents, which include (-)-OSU6162 and ACR16, have been shown to enhance locomotor activity in animals under conditions of low dopaminergic tone and to decrease activity when dopamine signaling is high, thus owing these drugs their name.4 The compounds reduce locomotor activity in amphetamine-treated animals, which is indicative of antipsychotic activity and have also been shown to reduce social withdrawal in the (+)-MK-801 rat model of negative symptoms in schizophrenia.6 Dopaminergic stabilizers have also shown clinical promise; the compound ACR16 (also known as pridopidine, or Huntexil) is currently in phase III clinical trials to treat Huntington's disease,5 and another dopaminergic stabilizer has completed a phase I trial to evaluate its efficacy in reducing L-DOPA-induced dyskinesia (Identifier: NCT01023282). In addition, (−)-OSU6162 and ACR16 have shown antipsychotic activity in patients.4

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Acknowledgements

This work has been supported by Research Grants from the Swedish Research Council (04x-715 to KF and 15083 to PÅ), Karolinska Institutet Grant (KI fonder 2011, to DM) and Stiftelsen Lars Hiertas Minne to KS.

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  1. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

    K Sahlholm, P Århem, K Fuxe & D Marcellino

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  1. K Sahlholm
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  2. P Århem
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  3. K Fuxe
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  4. D Marcellino
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Correspondence to D Marcellino.

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Sahlholm, K., Århem, P., Fuxe, K. et al. The dopamine stabilizers ACR16 and (−)-OSU6162 display nanomolar affinities at the σ-1 receptor. Mol Psychiatry 18, 12–14 (2013). https://doi.org/10.1038/mp.2012.3

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