Synthesis, characterization and in silico screening of potential biological activity of 17α-ethynyl-3β, 17β, 19-trihydroxyandrost-5-en acetylated derivatives

Ochoa, Ma. Eugenia; Farfán, Norberto; Soto-Castro, Delia; Santillán, Rosa

doi:10.1016/j.molstruc.2020.129167

Cited by 4 publications

(3 citation statements)

References 39 publications

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“…The average accuracy of prediction estimated in the leave-one-out cross-validation procedure (each drug is excluded from the training set and its activity predicted based on the spatial autoregressive model obtained on the rest of the training set) for the whole PASS training set was 95%, as in ref . This approach, widely used in pharmacology and toxicology to estimate potential drug effects, − evaluated the probability of NBPEAs tested here to exert a specific functional activity (Pa, %) in vivo and also compared these predictions to those for drugs analyzed by the AI phenotyping approach (described earlier), such as ketamine, PCP, MDMA, LSD, and THC.…”

Section: Methodsmentioning

confidence: 99%

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

Demin

Kupriyanova

Шевырин

et al. 2022

ACS Chem. Neurosci.

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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.

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Section: Methodsmentioning

confidence: 99%

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

Demin

Kupriyanova

Шевырин

et al. 2022

ACS Chem. Neurosci.

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“…Interestingly, the aforementioned lower static dipole moments for steroids 2 – 3 and 5 when compared to 1 , correlate effectively with higher contributions of dispersive C⋅⋅⋅H/H⋅⋅⋅H contacts ( 1 : 84.2 %, 2 : 91.9 %, 3 : 90.0 %, 5 : 89.2 %) as well as a with lower contributions of H⋅⋅⋅O contacts ( 1 : 14.5 %, 2 : 8.1 %, 3 : 10.0 %, 5 : 9.2 %), suggesting a correlation between the polarity of these steroidal frameworks and their proclivity to stablish polar/non polar supramolecular interactions. It should be noted that due to the complexity of the self‐assembly of large molecules into crystals, finding correlations of physicochemical properties at the molecular level with the observed crystal packing is a challenging task; [7e] the apparent relatively simple scenario in this case may come from the fact that in spite of the conformational differences in the A/B rings discussed earlier, the molecular shape/volume of compounds 1 – 3 and 5 are rather similar, providing an even scenario for differences in charge distribution to be manifested in the crystal packing.…”

Section: Resultsmentioning

confidence: 99%

A Steroidal Molecular Rotor with Fast Solid‐State Dynamics Obtained by Crystal Engineering: Role of the Polarity of the Stator

Labra‐Vázquez

Ochoa²,

Alfonso-Herrera³

et al. 2022

Eur J Org Chem

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A set of Steroidal Molecular Rotors (SMRs) were synthesized and characterized employing a Sonogashira cross-coupling reaction as the key synthetic step. The static dipole moment (μ 0 ) of the stator was examined as a crystal engineering criterium that could determine the easiness with which the rotator participates in the high energy supramolecular interactions that frequently preclude rotation in this class of molecular machines. The strategy is critically evaluated through theoretical/experimental analyses, featuring SXRD experiments and QM/MM computations of the rotational activation energy (Ea), allowing us to propose, within the systems studied, a potential correlation between the use of stators with lower μ 0 and a lowering of the Ea value. Results from solid-state NMR revealed that one of the most promising compounds indeed hosts fast rotational motion (above 25-30 kHz), standing as a rare example of a SMR with fast rotation within a crowded crystallographic environment.

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“…Average accuracy of prediction estimated in leave-one-out cross-validation procedure (each compound is excluded from the training set and its activity predicted based on SAR model obtained on the rest part of the training set) for the whole PASS training set is about 95% 126 . This approach is widely used by pharmacologists and toxicologists to estimate potential drug effects [127][128][129] . Here we evaluated the probability of studied 10 NBPEA compounds to have specific functional activity (Pa, %) in vivo also comparing these predictions to drugs studied in AI-driven phenotyping including ketamine, PCP, MDMA, LSD and THC.…”

Section: In Silico Molecular Modelingmentioning

confidence: 99%

Behavioral and neurochemical effects of novel N-Benzyl-2-phenylethylamine derivatives in adult zebrafish

Demin

Kupriyanova

Шевырин

et al. 2022

Preprint

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Serotonergic hallucinogenic drugs potently affect human brain and behavior, and have recently emerged as potentially promising agents in psychopharmacotherapy. Complementing rodent studies, zebrafish (Danio rerio) is a powerful animal model for screening neuroactive drugs, including serotonergic agents. Here, we test ten different 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 phenyl ring of N-benzyl fragment, assessing their behavioral and neurochemical effects in adult zebrafish. Overall, substitutions in N-benzyl fragment primarily affected zebrafish locomotion, and in phenethylamine moiety - anxiety-like behavior, also modulating brain serotonin and/or dopamine turnover. We also identified several behavioral clusters, 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)) agents. The 24H-NBOMe(F) and 34H-NBOMe(F) also reduced despair-like behavior in zebrafish. The artificial intelligence-driven phenotyping supports association of multiple compounds with NMDA antagonists and/or MDMA, supporting their potential hallucinogenic-like properties, as well as other valuable psychoactive effects. In silico functional molecular activity modelling also supports existing of similarities between studied NBOMes drugs, MDMA, and ketamine. Functional analysis implicates potential involvement of serotonin release stimulating activity, calcium channel (voltage-sensitive) activity, some serotonin receptors activity and variety of psychiatric and neurologic disorders treatments activities. Overall, we report potent neuroactive properties of several novel synthetic N-benzylphenylethylamines in an in vivo vertebrate model system (zebrafish), raising the possibility of their potential use in clinical practice.

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Synthesis, characterization and in silico screening of potential biological activity of 17α-ethynyl-3β, 17β, 19-trihydroxyandrost-5-en acetylated derivatives

Cited by 4 publications

References 39 publications

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

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

A Steroidal Molecular Rotor with Fast Solid‐State Dynamics Obtained by Crystal Engineering: Role of the Polarity of the Stator

Behavioral and neurochemical effects of novel N-Benzyl-2-phenylethylamine derivatives in adult zebrafish

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