Acute behavioral and Neurochemical Effects of Novel N -Benzyl-2-Phenylethylamine Derivatives in Adult Zebrafish

Novel N-benzyl-2-phenylethylamine (NBPEA) derivatives, with specific substitutions in the N-benzyl and phenethylamine moieties, alter locomotion and anxiety-like behavior in adult zebrafish. Substitutions in the N-benzyl moiety modulate locomotion, while those in the phenethylamine moiety affect anxiety-like behavior and brain serotonin or dopamine turnover. The 24H–NBOMe(F) and 34H–NBOMe(F) treatments reduced despair-like behavior. Computational analyses classified the agents into anxiogenic/hypolocomotor, behaviorally inert, anxiogenic/hallucinogenic-like, and anxiolytic/hallucinogenic-like clusters, with some NBPEAs showing behavioral similarity to conventional serotonergic and antiglutamatergic hallucinogens. These findings suggest potent neuroactive properties of several NBPEAs, indicating potential clinical use or abuse.

Study at a glance

Abstract

Hallucinogenic drugs potently affect brain and behavior and have also recently emerged as potentially promising agents in pharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful animal model organism for screening neuroactive drugs, including hallucinogens. Here, we test a battery of ten novel N-benzyl-2-phenylethylamine (NBPEA) derivatives with the 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the −OCH3, −OCF3, −F, −Cl, and −Br substitutions in the ortho position of the phenyl ring of the N-benzyl moiety, assessing their acute behavioral and neurochemical effects in the adult zebrafish. Overall, substitutions in the Overall, substitutions in the N-benzyl moiety modulate locomotion, and substitutions in the phenethylamine moiety alter zebrafish anxiety-like behavior, also affecting the brain serotonin and/or dopamine turnover. The 24H–NBOMe(F) and 34H–NBOMe(F) treatment also reduced zebrafish despair-like behavior. Computational analyses of zebrafish behavioral data by artificial intelligence identified several distinct clusters for these agents, including anxiogenic/hypolocomotor (24H–NBF, 24H–NBOMe, and 34H–NBF), behaviorally inert (34H–NBBr, 34H–NBCl, and 34H–NBOMe), anxiogenic/hallucinogenic-like (24H–NBBr, 24H–NBCl, and 24H–NBOMe(F)), and anxiolytic/hallucinogenic-like (34H–NBOMe(F)) drugs. Our computational analyses also revealed phenotypic similarity of the behavioral activity of some NBPEAs to that of selected conventional serotonergic and antiglutamatergic hallucinogens. In silico functional molecular activity modeling further supported the overlap of the drug targets for NBPEAs tested here and the conventional serotonergic and antiglutamatergic hallucinogens. Overall, these findings suggest potent neuroactive properties of several novel synthetic NBPEAs, detected in a sensitive in vivo vertebrate model system, the zebrafish, raising the possibility of their potential clinical use and abuse.