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

Summary

The lysergamide ECPLA, a close structural analog of LSD, binds with high affinity to serotonin, adrenergic, and dopamine receptors, and acts as a potent agonist at the 5-HT₂A receptor, which mediates psychedelic effects. In mice, ECPLA induced head twitches with an ED₅₀ of 317.2 nmol/kg, about 40% as potent as LSD. Two other analogs, LAMPA (ED₅₀ = 358.3 nmol/kg) and MIPLA (ED₅₀ = 421.7 nmol/kg), showed similar or slightly lower potency. These findings indicate that ECPLA, MIPLA, and LAMPA share pharmacological properties with LSD and other lysergamide hallucinogens.

Study at a glance

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-HT_2A 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-HT_2 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-HT_2A 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, α_2-adrenoceptors, and D_2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT_2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED_50) of 317.2 nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED_50 = 358.3 nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED_50 = 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.