Parallel artificial membrane permeability assay for blood–brain permeability determination of illicit drugs and synthetic analogues

Clemons, Kristina; Kretsch, Amanda; Verbeck, Guido F.

doi:10.1016/j.scijus.2014.06.004

Cited by 9 publications

(3 citation statements)

References 28 publications

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“… 37 Therefore, to determine whether the selected compound 3e could penetrate blood-brain barrier, a parallel artificial membrane penetration assay (PAMPA-BBB) was performed. 38 , 39 Firstly, the permeability of 10 commercial drugs was used to verify the method in Table 3 . A plot of experiment data versus the bibliographic values gave a good linear correlation: P e (exp.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease

Guo¹,

Xu²,

Cheng³

et al. 2022

DDDT

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Background Alzheimer’s disease (AD) belongs to neurodegenerative disease, and the increasing number of AD patients has placed a heavy burden on society, which needs to be addressed urgently. ChEs/MAOs dual-target inhibitor has potential to treat AD according to reports. Purpose To obtain effective multi-targeted agents for the treatment of AD, a novel series of hybrid compounds were designed and synthesized by fusing the pharmacophoric features of 3,4-dihydro-2 (1 H )-quinolinone and dithiocarbamate. Methods All compounds were evaluated for their inhibitory abilities of ChEs and MAOs. Then, further biological activities of the most promising candidate 3e were determined, including the ability to cross the blood-brain barrier (BBB), kinetics and molecular model analysis, cytotoxicity in vitro and acute toxicity studies in vivo. Results Most compounds showed potent and clear inhibition to AChE and MAOs. Among them, compound 3e was considered to be the most effective and balanced inhibitor to both AChE and MAOs (IC 50 =0.28 µM to eeAChE; IC 50 =0.34 µM to hAChE; IC 50 =2.81 µM to hMAO-B; IC 50 =0.91 µM to hMAO-A). In addition, 3e showed mixed inhibition of hAChE and competitive inhibition of hMAO-B in the enzyme kinetic studies. Further studies indicated that 3e could penetrate the BBB and showed no toxicity on PC12 cells and HT-22 cells when the concentration of 3e was lower than 12.5 µM. More importantly, 3e lacked acute toxicity in mice even at high dose (2500 mg/kg, P.O.). Conclusion This work indicated that compound 3e with a six-carbon atom linker and a piperidine moiety at terminal position was a promising candidate and was worthy of further study.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease

Guo¹,

Xu²,

Cheng³

et al. 2022

DDDT

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“…A parallel artificial membrane permeability assay blood brain barrier kit (Corning PAMPA 353015) was used to determine which tryptamines (both the proforms and “active”, dephosphorylated forms) were capable of passively permeating a blood brain barrier (BBB) mimetic (Chen et al, 2008; Clemons, Kretsch, & Verbeck, 2014). Following manufacturer’s protocol, identical concentrations (200 µM in PBS) of psilocybin, psilocin, norbaeocystin, 4-hydroxytryptamine (4-HT), baeocystin, norpsilocin, aeruginascin, 4-hydroxy-N,N,N- trimethyltryptamine (4-HO-TMT), and 5-HT (Serotonin HCl; Sigma H9523) were placed into a “donor” well (300µL) and separate permeability control acceptor wells, in triplicate, on a 96-well microplate containing a semi-permeable, lipid-coated membrane that separated compounds from an “acceptor” well filled with an identical buffer (PBS, 7.4 pH, room temperature).…”

Section: Methodsmentioning

confidence: 99%

“…Demonstrating that these tryptamines are dephosphorylated via alkaline phosphatase would provide insight into their activation dynamics and additional confirmation of analogous pharmacology. Further, confirming that the dephosphorylated forms of these compounds can passively permeate a biological membrane would provide evidence of their ability to enter the brain wherein they may exert psychoactive effects (Clemons, Kretsch, & Verbeck, 2014). Additionally, it has not yet been determined if the active, dephosphorylated forms of these tryptamines are deaminated by monoamine oxidase A (MAO-A), like psilocin.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological and behavioral effects of tryptamines present in psilocybin-containing mushrooms

Rakoczy,

Runge,

Sen

et al. 2023

Preprint

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Demand for more efficacious antidepressants, particularly those with a rapid onset of action, has resulted in a reevaluation of psychedelic drugs for their therapeutic potential. Several tryptamines found in psilocybin-containing 'magic' mushrooms share chemical similarities with psilocybin, and early work suggests they may also share receptor targets. However, few studies have explored their pharmacological and behavioral effects. To accomplish this, we compared baeocystin, norbaeocystin, and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, penetrate the blood brain barrier, serve as ligands for similar centrally located receptors, and modulate behavior in rodents similarly. We first assessed the stability and optimal storage and handling conditions for each compound. In vitro enzyme kinetics assays then found that all compounds shared nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin could cross a blood brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. Behaviorally, only psilocybin was found to induce head twitch responses in rats, a marker of 5HT2A agonism and indicator of the compound's hallucinogenic potential. However, like psilocybin, norbaeocystin was also found to improve outcomes in the forced swim test. All compounds were found to cause minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. Collectively, this work suggests that other naturally-occurring tryptamines, especially norbaeocystin, may share the same therapeutic potential as psilocybin, but without causing hallucinations.

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Neuroscience in Nigeria: the past, the present and the future

2017

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The science of the brain and nervous system cuts across almost all aspects of human life and is one of the fastest growing scientific fields worldwide. This necessitates the demand for pragmatic investment by all nations to ensure improved education and quality of research in Neurosciences. Although obvious efforts are being made in advancing the field in developed societies, there is limited data addressing the state of neuroscience in sub-Saharan Africa. Here, we review the state of neuroscience development in Nigeria, Africa's most populous country and its largest economy, critically evaluating the history, the current situation and future projections. This review specifically addresses trends in clinical and basic neuroscience research and education. We conclude by highlighting potentially helpful strategies that will catalyse development in neuroscience education and research in Nigeria, among which are an increase in research funding, provision of tools and equipment for training and research, and upgrading of the infrastructure at hand.

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Parallel artificial membrane permeability assay for blood–brain permeability determination of illicit drugs and synthetic analogues

Cited by 9 publications

References 28 publications

Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease

Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer’s Disease

Pharmacological and behavioral effects of tryptamines present in psilocybin-containing mushrooms

Neuroscience in Nigeria: the past, the present and the future

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