Multi-Functional Monoamine Oxidase and Cholinesterase Inhibitors for the Treatment of Alzheimer’s Disease
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
A potent MAO-B inhibiting analog of 2-acetyl-5-alkoxyphenol (IC50 = 2.9 nM) has recently been shown to positively affect learning and memory symptoms in AD animal models (Legoabe et al., 2015). Benzylamine side chains such as benzylpiperazine and N-methylbenzylamine derivatives has been shown to be active pharmacophoric groups for AChE inhibition (Sang et al., 2015). It is in light of this that Sang et al. (2017a) combined 2-acetylphenol with different length and functionalised benzylamine fragments to design a series of MTDLs. All the target compounds were selective AChE inhibitors with IC50 values ranging from 0.96 to 57.0 μM. Notably a longer methylene chain with piperidine and pyrrolidine terminal groups resulted in good activity. The opposite, however, was observed with regard to MAO inhibition. A satisfactory balance for the two enzymes was achieved with compound 27 (Fig. 11.21), a mixed type inhibitor that binds to both the CAS and PAS of AChE and acts as selective inhibitor of MAO-B (IC50 = 6.8 μM). Moreover, 27 showed the ability to act as an antioxidant, neuroprotectant and selective metal chelating agent in relevant assays (Sang et al., 2017a).
Licit and illicit drugs
Jason Payne-James, Richard Jones in Simpson's Forensic Medicine, 2019
1-Benzylpiperazine (BZP) is a stimulant. It is sold as an alternative to amphetamine, methamphetamine and MDMA and, on occasion, is misrepresented as MDMA. It interacts with numerous different receptors, but the net effect produced more or less resembles that of an amphetamine-type drug. Consequently, the adverse effects associated with BZP use are likely to include confusion, agitation, vomiting, anxiety and palpitations. There is strong evidence that higher plasma levels of BZP are associated with an increased incidence of seizures. Co-ingestion of ethanol increases the likelihood of adverse BZP-induced symptoms, but reduces the incidence of BZP seizures.
Comparing the dopaminergic neurotoxic effects of benzylpiperazine and benzoylpiperazine
Published in Toxicology Mechanisms and Methods, 2018
Daniel P. Katz, Mohammed Majrashi, Sindhu Ramesh, Manoj Govindarajulu, Dwipayan Bhattacharya, Subhrajit Bhattacharya, Aimen Shlghom, Chastity Bradford, Vishnu Suppiramaniam, Jack Deruiter, C. Randall Clark, Muralikrishnan Dhanasekaran
Synthesis of Benzylpiperazine and Benzoylpiperazine: A mixture of benzaldehyde (1 g, 0.01 mol) and piperazine (1.43 g, 0.0165 mol) in methanol was stirred for half an hour. Then sodium cyanoborohydride (2.1 g, 0.033 mol) was added and the mixture was allowed to stir for half an hour. The reaction was quenched by adding ice/water mixture and stirring the mixture for 20 min followed by extracting the final product using dichloromethane (3 × 30 ml). The combined organic extract was dried with anhydrous magnesium sulfate, filtered and evaporated to yield yellow oil. The oil was dissolved in anhydrous diethyl ether, and hydrochloric acid was added to form the hydrochloride salt. Benzoyl chloride (1.4 g, 0.01 mol) was dissolved in dichloromethane and the solution was dripped slowly over the piperazine solution over 10 min. The mixture was allowed to stir for 15 min. The solution was evaporated under reduced pressure to yield light yellow oil. The oil was dissolved in anhydrous diethyl ether, and hydrochloric acid gas was added to form the hydrochloride salt (Figure 1).
Flibanserin toxicity in a toddler following ingestion
Published in Clinical Toxicology, 2018
Nicholas Granzella, Betty C. Chen, Geoffrey S. Baird, Matthew Valento
The primary metabolic pathway of flibanserin involves action by CYP3A4 in the liver. TFMPP has been identified as an active metabolite of flibanserin, and is detectable via a GC-MS assay available at our institution (Figure 1) [4,5]. TFMPP is used recreationally as a stimulant and hallucinogen often in combination with an analogue benzylpiperazine (BZP) [6]. These drugs are known colloquially as “Legal X”, or more generally “Molly” or “Ecstasy [7].” They are used as alternatives to 3,4-methylenedioxymethamphetamine (MDMA) [6]. TFMPP was identified in the 1970s as a serotonergic metabolite of antrafenine, which was previously developed as an analgesic and anti-inflammatory agent [6]. As a class, piperazine compounds such as TFMPP have been described as causing hyperthermia, muscle rigidity, brain edema, seizures, hallucinations, psychosis, tachycardia, hypertension, and nausea, among others [8,9]. Serotonin syndrome and increases in NE levels have also been described following piperazine use [10,11]. With an elevated TFMPP concentration in the context of flibanserin ingestion, clinical effects typical of the piperazine class may develop and may have caused our patient to have seizure-like activity, mild hypertension, mydriasis, and drug-induced hyperthermia. Alternatively, other possible etiologies of the increased temperature could include occult infectious process and/or stress response (e.g., to hospitalization).
Novel approaches to the discovery of selective human monoamine oxidase-B inhibitors: is there room for improvement?
Published in Expert Opinion on Drug Discovery, 2019
Paolo Guglielmi, Simone Carradori, Alessandra Ammazzalorso, Daniela Secci
Increasing the dimension of the alkyl chain and placing piperidine as terminal moiety produced weak inhibitors of hMAO-B, while better results were exhibited by compounds possessing 4-benzylpiperidine. However, the IC50 values were in the micromolar range, with the best outcome obtained with coumarin ring decorated with chloro and methyl substituents, respectively, at C3 and C4 (IC50 = 0.29 µM). Finally, the insertion of N-benzylpiperazine produced the drop of inhibitory activity with high micromolar inhibition of hMAO-B. The binding mode of the most active compound was explored by docking studies, showing that the coumarin moiety binds to in the polar region of the substrate cavity next to the FAD cofactor and the ‘aromatic sandwich’ defined by Tyr398 and Tyr435. The benzyl- and N-benzylpiperidine side chains were located inside the hydrophobic environment of the entrance cavity, where they were stabilized by van der Waals interactions.
Related Knowledge Centers
- Amphetamine
- Anthelmintic
- Clinical Trial
- Piperazine
- Psychosis
- Stimulant
- Euphoria
- Kidney
- Recreational Drug Use
- Seizure