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

  • Adam L. Halberstadt
  • Landon M. Klein
  • Muhammad Chatha
  • Laura B. Valenzuela
  • Alexander Stratford
  • Jason Wallach
  • David E. Nichols
  • Simon D. Brandt
Original Investigation

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.

Keywords

LSD 5-HT2A receptor Lysergamide Psychedelics Head twitch 

Notes

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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018

Authors and Affiliations

  • Adam L. Halberstadt
    • 1
    • 2
  • Landon M. Klein
    • 1
  • Muhammad Chatha
    • 1
  • Laura B. Valenzuela
    • 1
  • Alexander Stratford
    • 3
  • Jason Wallach
    • 4
  • David E. Nichols
    • 5
  • Simon D. Brandt
    • 6
  1. 1.Department of PsychiatryUniversity of California San DiegoLa JollaUSA
  2. 2.Research ServiceVA San Diego Healthcare SystemSan DiegoUSA
  3. 3.Synex Synthetics BVMaastrichtThe Netherlands
  4. 4.Department of Pharmaceutical Sciences, Philadelphia College of PharmacyUniversity of the SciencesPhiladelphiaUSA
  5. 5.Division of Chemical Biology and Medicinal ChemistryUniversity of North Carolina, Genetic Medicine BuildingChapel HillUSA
  6. 6.School of Pharmacy and Biomolecular SciencesLiverpool John Moores UniversityLiverpoolUK

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