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

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 −OCH 3 , −OCF 3 , −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.

Chronic Behavioral and Neurochemical Effects of Four Novel N-Benzyl-2-phenylethylamine Derivatives Recently Identified as “Psychoactive” in Adult Zebrafish Screens

“…The drugs were purified using flash chromatography on high-purity Merck silica gel (9385, 60 Å, 230–400 mesh), yielding white powder hydrochlorides. Analytical data used in this study was reported previously. , …”

“…Their ability to cross the zebrafish blood-brain barrier and enter the brain as well as chemical synthesis, chemical structures, and analytical data have already been reported previously. − Typically, in the 25X-NBOMe conventional nomenclature, the X (i.e., H for hydrogen here) indicates the substitution at position 4 of the phenethylamine moiety. , However, as 24H- and 34H- isomers carry a methoxy group at this position, they can also be described as 24- and 34-NBOMes, respectively . Here, we will specifically use the latter nomenclature, aiming at a greater clarity in order to emphasize that no other substitutions (beyond the two methoxy groups) were introduced at the phenyl ring of the phenethylamine moiety (also see similar examples in refs , , and ).…”

“…70−73 Typically, in the 25X-NBOMe conventional nomenclature, the X (i.e., H for hydrogen here) indicates the substitution at position 4 of the phenethylamine moiety. 70,74 However, as 24H-and 34Hisomers carry a methoxy group at this position, they can also be described as 24-and 34-NBOMes, respectively. 70 Here, we will specifically use the latter nomenclature, aiming at a greater Given the growing concerns over synthetic hallucinogenic drug use and abuse, it is critical to understand more fully their long-term chronic use in vivo.…”

“…70,74 However, as 24H-and 34Hisomers carry a methoxy group at this position, they can also be described as 24-and 34-NBOMes, respectively. 70 Here, we will specifically use the latter nomenclature, aiming at a greater Given the growing concerns over synthetic hallucinogenic drug use and abuse, it is critical to understand more fully their long-term chronic use in vivo. The present study aims to characterize behavioral and neurochemical profiles of 24H-NBOMe(F), 34H-NBOMe(F), 34H-NBF, and 34H-NBCl following their chronic 14 day exposure to adult zebrafish, probing CNS activity and assessing the potential of these novel NBOMes as putative CNS therapies.…”

Embryonic exposure to fentanyl induces behavioral changes and neurotoxicity in zebrafish larvae

“…The zebrafish (Danio rerio) has been widely employed in genetic and developmental research in recent years ( Bailey, Oliveri & Levin, 2013 ). With the varying chemical structures of new psychoactive substances, such as synthetic cannabinoids ( Garcia-Gonzalez et al, 2021 ), synthetic opioids ( Kolesnikova et al, 2021 ), and hallucinogenic drugs ( Demin et al, 2022 ), the zebrafish model provides an efficient and rapid method to study the toxicity assessment and mechanisms of these compounds. Zebrafish have homologous opioidergic genes to humans and a diverse behavioral profile that can be used to validate the neurotoxicity generated by opioids ( Stevens, 2009 ; Demin et al, 2018 ).…”