Impure but not inactive: Behavioral pharmacology of dibenzylpiperazine, a common by-product of benzylpiperazine synthesis

Background: Substituted piperazines comprise a substantial proportion of the novel psychoactive substance market. Among the most widely abused piperazine compounds are meta-chlorophenylpiperazine (mCPP), tri-fluoromethylphenylpiperazine (TFMPP), and, especially, benzylpiperazine (BZP), which are commonly incorporated, either alone or in combination, in illicit “party pills” or “ecstasy” formulations. Illicit synthesis of BZP often results in production of an impure by-product dibenzylpiperazine (DBZP), which frequently appears alongside BZP in these formulations; however, despite its ubiquity, little information exists regarding the abuse liability of DBZP. Aims: The current study aimed to evaluate the abuse-related behavioral pharmacology of DBZP. Methods: DBZP, mCPP, and TFMPP were tested in parallel in mice in locomotor activity and conditioned place preference assays, and in a drug discrimination assay with rats trained to discriminate either methamphetamine, cocaine, (±)-3,4-methylenedioxymethamphetamine (MDMA), or -2,5-dimethoxy-4-methylamphetamine(DOM). Results: Each of the compounds tested produced dose-dependent decreases in locomotor activity. DBZP substituted fully for methamphetamine, produced subthreshold drug-appropriate responding for cocaine and MDMA, and failed to substitute for DOM. Conversely, TFMPP and mCPP only produced subthreshold drug-appropriate responding for methamphetamine and MDMA, respectively, and both compounds failed to substitute for cocaine or DOM. None of the compounds tested produced a place preference. DBZP produced convulsions in rats at the highest dose tested. Conclusions: These data indicate that DBZP is more similar to BZP, albeit with lower potency and efficacy, than its serotonergic piperazine counterparts, and is a behaviorally-active compound with some abuse liability and potential for adverse health effects.

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Examination of the Novel Sigma-1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti-allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use

International Journal of Molecular Sciences ◽

10.3390/ijms23020615 ◽

2022 ◽

Vol 23 (2) ◽

pp. 615

Author(s):

Lisa L. Wilson ◽

Shainnel O. Eans ◽

Insitar Ramadan-Siraj ◽

Maria N. Modica ◽

Giuseppe Romeo ◽

...

Keyword(s):

Neuropathic Pain ◽

Locomotor Activity ◽

Adverse Effects ◽

Conditioned Place Preference ◽

Place Preference ◽

Drug Reinforcement ◽

Sigma 1 Receptor ◽

Sigma 1 ◽

Preclinical And Clinical Studies ◽

Dose Dependent

Neuropathic pain is a significant problem with few effective treatments lacking adverse effects. The sigma-1 receptor (S1R) is a potential therapeutic target for neuropathic pain, as antagonists for this receptor effectively ameliorate pain in both preclinical and clinical studies. The current research examines the antinociceptive and anti-allodynic efficacy of SI 1/28, a recently reported benzylpiperazine derivative and analog of the S1R antagonist SI 1/13, that was 423-fold more selective for S1R over the sigma-2 receptor (S2R). In addition, possible liabilities of respiration, sedation, and drug reinforcement caused by SI 1/28 have been evaluated. Inflammatory and chemical nociception, chronic nerve constriction injury (CCI) induced mechanical allodynia, and adverse effects of sedation in a rotarod assay, conditioned place preference (CPP), and changes in breath rate and locomotor activity were assessed after i.p. administration of SI 1/28. Pretreatment with SI 1/28 produced dose-dependent antinociception in the formalin test, with an ED50 (and 95% C.I.) value of 13.2 (7.42–28.3) mg/kg, i.p. Likewise, SI 1/28 produced dose-dependent antinociception against visceral nociception and anti-allodynia against CCI-induced neuropathic pain. SI 1/28 demonstrated no impairment of locomotor activity, conditioned place preference, or respiratory depression. In summary, SI 1/28 proved efficacious in the treatment of acute inflammatory pain and chronic neuropathy without liabilities at therapeutic doses, supporting the development of S1R antagonists as therapeutics for chronic pain.

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Neurochemical and Behavioral Effects of a New Hallucinogenic Compound 25B-NBOMe in Rats

Neurotoxicity Research ◽

10.1007/s12640-020-00297-8 ◽

2020 ◽

Author(s):

Adam Wojtas ◽

Monika Herian ◽

Mateusz Skawski ◽

Małgorzata Sobocińska ◽

Alejandro González-Marín ◽

...

Keyword(s):

Locomotor Activity ◽

Comet Assay ◽

Short Term Memory ◽

Glutamate Release ◽

Anxiolytic Effect ◽

Brain Regions ◽

The Novel ◽

Object Recognition Test ◽

Wide Range ◽

Dose Dependent

Abstract4-Bromo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25B-NBOMe) is a hallucinogen exhibiting high binding affinity for 5-HT2A/C serotonin receptors. In the present work, we investigated its effect on dopamine (DA), serotonin (5-HT), acetylcholine (ACh), and glutamate release in the rat frontal cortex, striatum, and nucleus accumbens. Hallucinogenic activity, impact on cognitive and motor functions, and anxiogenic/anxiolytic properties of this compound were also tested. The release of DA, 5-HT, ACh, and glutamate was studied using microdialysis in freely moving animals. Hallucinogenic activity was investigated using head and body twitch response (WDS), cognitive functions were examined with the novel object recognition test (NOR), locomotor activity was studied in the open field (OF), while anxiogenic/anxiolytic effect was tested using the light/dark box (LDB). Neurotoxicity was evaluated with the comet assay. 25B-NBOMe increased DA, 5-HT, and glutamate release in all studied brain regions, induced hallucinogenic activity, and lowered the recognition index (Ri) vs. control in the NOR test. It also decreased locomotor activity of rats in the OF test. The effect of 25B-NBOMe in the NOR test was inhibited by scopolamine. In the LDB test, the time spent in the dark zone was longer in comparison to control and was dose-dependent. In contrast to MDMA, 25B-NBOMe showed subtle genotoxic effect observed in the comet assay.Our findings indicate that 25B-NBOMe shows hallucinogenic activity in the wide range of doses. The changes in neurotransmitter levels may be related to 25B-NBOMe affinity for 5-HT2A receptor. Alterations in the NOR, OF, and LDB indicate that 25B-NBOMe impacts short-term memory, locomotion, and may be anxiogenic.

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Cytocompatibility of stabilized black phosphorus nanosheets tailored by directly conjugated polymeric micelles for human breast cancer therapy

Scientific Reports ◽

10.1038/s41598-021-88791-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

M. Biedulska ◽

P. Jakóbczyk ◽

M. Sosnowska ◽

B. Dec ◽

A. Muchlińska ◽

...

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Polymeric Micelles ◽

Black Phosphorus ◽

Environmental Stability ◽

Breast Cancer Cell Lines ◽

The Novel ◽

Ft Ir ◽

Dose Dependent ◽

Aggressive Breast Cancer

AbstractThe novel procedure of few-layer black phosphorus (FLBP) stabilization and functionalisation was here proposed. The cationic polymer PLL and non-ionic PEG have been involved into encapsulation of FLBP to allow sufficient time for further nanofabrication process and overcome environmental degradation. Two different spacer chemistry was designed to bind polymers to tumor-homing peptides. The efficiency of functionalisation was examined by RP-HPLC, microscopic (TEM and SEM) and spectroscopic (FT-IR and Raman) techniques as well supported by ab-initio modelling. The cell and dose dependent cytotoxicity of FLBP and its bioconjugates was evaluated against HB2, MCF-7 and MDA-MB-231 cell lines. Functionalisation allowed not only for improvement of environmental stability, but also enhances therapeutic effect by abolished the cytotoxicity of FLBP against HB2 cell line. Moreover, modification of FLBP with PLL caused increase of selectivity against highly aggressive breast cancer cell lines. Results indicate the future prospect application of black phosphorus nanosheets as nanocarrier, considering its unique features synergistically with conjugated polymeric micelles.

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The dose‐dependent analgesic effects, abuse liability, safety and tolerability of oral cannabidiol in healthy humans

British Journal of Clinical Pharmacology ◽

10.1111/bcp.14973 ◽

2021 ◽

Author(s):

Caroline A. Arout ◽

Margaret Haney ◽

Evan S. Herrmann ◽

Gillinder Bedi ◽

Ziva D. Cooper

Keyword(s):

Abuse Liability ◽

Analgesic Effects ◽

Healthy Humans ◽

Dose Dependent

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Effects of β-funaltrexamine and naloxonazine on single-trial morphine-conditioned place preference and locomotor activity

Pharmacology Biochemistry and Behavior ◽

10.1016/s0091-3057(02)01049-3 ◽

2003 ◽

Vol 74 (3) ◽

pp. 617-622 ◽

Cited By ~ 9

Author(s):

M.T Bardo ◽

B.J Gehrke ◽

B.E Shortridge ◽

A.S Rauhut

Keyword(s):

Locomotor Activity ◽

Conditioned Place Preference ◽

Place Preference ◽

Single Trial

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The novel psychoactive substance 3-methylmethcathinone (3-MMC or metaphedrone): A review

Forensic Science International ◽

10.1016/j.forsciint.2018.11.024 ◽

2019 ◽

Vol 295 ◽

pp. 54-63 ◽

Cited By ~ 8

Author(s):

Bárbara Ferreira ◽

Diana Dias da Silva ◽

Félix Carvalho ◽

Maria de Lourdes Bastos ◽

Helena Carmo

Keyword(s):

The Novel ◽

Psychoactive Substance ◽

Novel Psychoactive Substance

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The Effect of the mGlu8 Receptor Agonist, S-3,4-DCPG on Acquisition and Expression of Morphine-induced Conditioned Place Preference in Male rats

10.21203/rs.3.rs-114995/v2 ◽

2021 ◽

Author(s):

Nazanin Kahvandi ◽

Zahra Ebrahimi ◽

Seyed Asaad Karimi ◽

Siamak Shahidi ◽

Iraj Salehi ◽

...

Keyword(s):

Conditioned Place Preference ◽

Metabotropic Glutamate Receptors ◽

Preference Test ◽

Place Preference ◽

Male Rats ◽

Dependent Manner ◽

Metabotropic Glutamate ◽

Male Wistar Rats ◽

Dose Dependent

Abstract Background: The nucleus accumbens (NAc) plays a principal role in drug reward. It has been reported that metabotropic glutamate receptors (mGlu receptors) play a key role in the rewarding pathway(s). Previous studies have shown the vast allocation of the different types of mGlu receptors, including mGlu8 receptors, in regions that are associated with opioid rewards, such as the NAc. The aim of the present study was to evaluate the role of mGlu8 receptors within the NAc in the acquisition and expression phases of morphine induced conditioned place preference (CPP). Adult male Wistar rats were bilaterally implanted by two cannulas' in the NAc and were evaluated in a CPP paradigm. Selective mGlu8 receptor allosteric agonist (S-3,4-DCPG) was administered at doses of 0.03, 0.3, and 3 μg/0.5 μL saline per side into the NAc on both sides during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase, or before place preference test, or post-conditioning (expression) phase of morphine-induced CPP. Results: The results revealed that intra-accumbal administration of S-3,4-DCPG (0.3 and 3 μg) markedly decreased the acquisition in a dose-dependent manner but had no effect on expression of morphine-induced CPP. Conclusions: The findings suggest that activation of mGlu8 receptors in the NAc dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine which may be related to the glutamate activity into the NAc and in reward pathway(s). These data suggest that mGlu8 receptor may be involved in conditioned morphine reward.

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Pharmacological activity of new imidazole-4,5-dicarboxylic acid derivatives in dopaminergic transmission suppression ttests in mice and rats

Research Results in Pharmacology ◽

10.3897/rrpharmacology.6.57883 ◽

2020 ◽

Vol 6 (4) ◽

pp. 51-57

Author(s):

Ekaterina E. Yakovleva ◽

Eugeny R. Bychkov ◽

Maria M. Brusina ◽

Levon B. Piotrovsky ◽

Petr D. Shabanov

Keyword(s):

Locomotor Activity ◽

Dicarboxylic Acid ◽

Open Field ◽

Field Test ◽

Open Field Test ◽

Dicarboxylic Acids ◽

Dopaminergic Transmission ◽

Dose Dependent ◽

Derivatives Of ◽

Experimental Improvement

Objective: To study the antiparkinsonian activity of new 1,2-substituted imidazole-4,5-dicarboxylic acids in dopaminergic transmission suppression tests in mice and rats. Materials and methods: On a model of reserpine extrapyramidal disorders, the derivatives of imidazole-dicarboxylic acids (IEM2258, IEM2248, IEM2247) were injected into the lateral brain ventricles of the mice 30 minutes after injecting reserpine at the doses of 0.1–0.5 mmol. Locomotor activity was analyzed in the Open-field test 2 hours later. In the catalepsy model, the studied agents were injected, using a pre-implanted cannula, with a simultaneous intraperitoneal injection of haloperidol. The severity of catalepsy was assessed with the Morpurgo method. Amantadine was used as a comparator drug in all the tests. Results: It was shown that IEM2258 significantly increased the main indicators of locomotor activity in the Open-field test at all the studied doses. The value of the antiparkinsonian effect of IEM2258 at doses of 0.4–0.5 mmol significantly exceeded that of amantadine. The antiparkinsonian effect of IEM2247 was maximally expressed and was significantly different from those in the control and comparator group at doses of 0.2 and 0.3 mmol. For all the experimental groups, a significant decrease in the manifestations of catalepsy in comparison with control indexes was determined. Discussion: The results made it possible to suggest the involvement of imidazole-4,5-dicarboxylic acids derivatives in the process of experimental improvement of dopaminergic neuromodulation and efficiency in animals. Conclusion: The data showed a significant dose-dependent antiparkinsonian activity of new imidazole-4,5-dicarboxylic acid derivatives, which makes it promising to develop these agents and to further search for effective and safe antiparkinsonian drugs in this pharmacological class. Graphical abstract

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