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2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors

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Abstract

Rationale

Over the last decade, many new psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Another class of designer drugs is derived from the 2-aminoindan structural template. Several members of this class, including the parent compound 2-aminoindan (2-AI), have been sold as designer drugs. Another aminoindan derivative, 5-methoxy-2-aminoindan (5-MeO-AI or MEAI), is the active ingredient in a product marketed online as an alcohol substitute.

Methods

Here, we tested 2-AI and its ring-substituted derivatives 5-MeO-AI, 5-methoxy-6-methyl-2-aminoindan (MMAI), and 5,6-methylenedioxy-2-aminoindan (MDAI) for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We also compared the binding affinities of the aminoindans at 29 receptor and transporter binding sites.

Results

2-AI was a selective substrate for NET and DAT. Ring substitution increased potency at SERT while reducing potency at DAT and NET. MDAI was moderately selective for SERT and NET, with tenfold weaker effects on DAT. 5-MeO-AI exhibited some selectivity for SERT, having sixfold lower potency at NET and 20-fold lower potency at DAT. MMAI was highly selective for SERT, with 100-fold lower potency at NET and DAT. The aminoindans had relatively high affinity for α2-adrenoceptor subtypes. 2-AI had particularly high affinity for α2C receptors (Ki = 41 nM) and slightly lower affinity for the α2A (Ki = 134 nM) and α2B (Ki = 211 nM) subtypes. 5-MeO-AI and MMAI also had moderate affinity for the 5-HT2B receptor.

Conclusions

2-AI is predicted to have (+)-amphetamine-like effects and abuse potential whereas the ring-substituted derivatives may produce 3,4-methylenedioxymethamphetamine (MDMA)-like effects but with less abuse liability.

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Acknowledgments

Receptor binding data were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program (NIMH PDSP), Contract # HHSN-271-2008-00025-C. The NIMH PDSP is directed by Dr. Bryan Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda, MD, USA. Principles of laboratory animal care were followed for these experiments, as well as national laws.

Funding

This work was supported by the National Institute on Drug Abuse (NIDA) Intramural Research Program DA 00523, NIDA Grant R01 DA041336, and by the Veteran’s Administration VISN 22 Mental Illness Research, Education, and Clinical Center.

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Authors and Affiliations

  1. Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0804, USA

    Adam L. Halberstadt

  2. Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA, 92161, USA

    Adam L. Halberstadt

  3. School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK

    Simon D. Brandt

  4. Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA

    Donna Walther & Michael H. Baumann

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  1. Adam L. Halberstadt
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Correspondence to Adam L. Halberstadt.

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Halberstadt, A.L., Brandt, S.D., Walther, D. et al. 2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors. Psychopharmacology 236, 989–999 (2019). https://doi.org/10.1007/s00213-019-05207-1

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