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Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA)

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A Correction to this article was published on 15 November 2018

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Abstract

Rationale

The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds.

Objective

In this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens.

Methods

Competitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes.

Results

ECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2 nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3 nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7 nmol/kg) was slightly less potent than ECPLA.

Conclusions

These findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens.

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Change history

  • 15 November 2018

    The author of this article wanted to change the Acknowledgments section to: These studies were supported by an award from NIDA (R01 DA041336), as well as by the Veteran’s Administration VISN 22 Mental Illness Research, Education, and Clinical Center. Receptor binding and functional data were generously

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Acknowledgments

These studies were supported by an award from NIDA (R01 DA041336), as well as by the Veteran’s Administration VISN 22 Mental Illness Research, Education, and Clinical Center. Receptor binding data were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program (NIMH PDSP), Contract No. 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.

Funding

This study was funded by NIDA (R01 DA041336).

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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, Landon M. Klein, Muhammad Chatha & Laura B. Valenzuela

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

    Adam L. Halberstadt

  3. Synex Synthetics BV, Karveelweg 20, 6222, NH, Maastricht, The Netherlands

    Alexander Stratford

  4. Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, 600 South 43rd Street, Philadelphia, PA, 19104, USA

    Jason Wallach

  5. Division of Chemical Biology and Medicinal Chemistry, University of North Carolina, Genetic Medicine Building, 120 Mason Farm Road, Chapel Hill, NC, 27599, USA

    David E. Nichols

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

    Simon D. Brandt

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

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Halberstadt, A.L., Klein, L.M., Chatha, M. et al. Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA). Psychopharmacology 236, 799–808 (2019). https://doi.org/10.1007/s00213-018-5055-9

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