Comparative Interactions of Anesthetic Alkylphenols with Lipid Membranes

Tsuchiya, Hironori; Mizogami, Maki

doi:10.4236/ojanes.2014.412044

Cited by 10 publications

(11 citation statements)

References 39 publications

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“…Chemical seizure models are widely used in preclinical evaluation of drugs’ anticonvulsant properties [ 18 ]. Bearing in mind the fact that both carvacrol and guaiacol allosterically positively modulate GABA A receptors [ 5 ] the convulsive behavior of experimental animals was induced by convulsant pentylenetetrazole (PTZ) which is GABA receptor agonist. Carvacrol and guaiacol esters of GABA were screened for its anticonvulsant potential trough PTZ test that represents a valid model for human generalized myoclonic seizures.…”

Section: Resultsmentioning

confidence: 99%

“…For example, thymol and carvacrol can activate TRPV1 and TRPV3 ion channels; guaiacol may exert its antinociceptive effects via TRPV1; menthol was found to be a TRPM8 agonist [ 3 ]. Furthermore, the abovementioned monocyclic terpenes are active within the CNS and act as positive allosteric modulators of GABA A receptors showing a variety of effects such as anticonvulsant, analgesic and nootropic actions [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Pharmacological Properties of Novel Esters Based on Monocyclic Terpenes and GABA

Nesterkina

Kravchenko

2016

Pharmaceuticals

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Novel esters of γ-aminobutyric acid (GABA) with monocyclic terpenes were synthesized via Steglich esterification and characterized by 1H-NMR, IR and mass spectral studies. Their anticonvulsant, analgesic and anti-inflammatory activities were evaluated by a PTZ-induced convulsion model, AITC-induced hyperalgesia and AITC-induced paw edema, respectively. All studied esters, as well as their parent terpenes, were found to produce antinociceptive effects in the AITC-induced model and attenuate acute pain more than the reference drug benzocaine after their topical application. GABA esters of l-menthol and thymol were also shown to exceed the reference drug ibuprofen in their ability to decrease the inflammatory state induced by intraplantar injection of the TRPA1 activator AITC. The present findings indicate that GABA esters of carvacrol and guaiacol are not a classical prodrug and possess their own pharmacological activity. Prolonged antiseizure action of the ester based on the amino acid and guaiacol (200 mg/kg) was revealed at 24 h after oral administration. Furthermore, orally co-administered gidazepam (1 mg/kg) and GABA esters of l-menthol, thymol and carvacrol produce synergistic seizure prevention effects.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Pharmacological Properties of Novel Esters Based on Monocyclic Terpenes and GABA

Nesterkina

Kravchenko

2016

Pharmaceuticals

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“…Thymol from thyme (Thymus vulgaris, Lamiaceae) and menthol from peppermint (Mentha piperita, Lamiaceae) or spearmint (Mentha spicata, Lamiaceae) positively allosterically modulate GABA A receptors [37][38][39]. Several studies showed that thymol and menthol interact with lipid membranes to modify their physicochemical properties [9, [40][41][42]. Reiner et al [40] compared the effects of GABAergic phenols on dipalmitoylphosphatidylcholine Langmuir films.…”

Section: Phytochemicalsmentioning

confidence: 99%

“…By 1 Hnuclear magnetic resonance spectroscopy, they revealed that thymol and propofol insert into phosphatidylcholine unilamellar vesicles and locate in the region between the choline polar group, the glycerol and the acyl chain first atom. In DPH fluorescence polarization experiments of Tsuchiya and Mizogami [42], thymol, propofol and their related alkylphenols structurespecifically increased the fluidity of neuromimetic membranes prepared with phospholipids and cholesterol at 1-10 μM. Menthol also has the property to fluidize the similar neuro-mimetic membranes at 50 μM [9].…”

Section: Phytochemicalsmentioning

confidence: 99%

Membrane Interactivity Shared by Receptor- Acting Drugs

Tsuchiya

2019

JAMPS

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Background: Although lipids have been regarded as a passive component to constitute biomembranes, they can also play an important role in modulation of the activity or function of membrane-embedded proteins like receptors. Membrane lipids are presumed to be one of additional sites of action for receptor-acting drugs because their broad pharmacological spectra are not necessarily interpretable by the direct action on receptors. In order to obtain novel insights into the drug target and mechanism, we reviewed the membrane interactivity of different classes of drugs to act on representative receptors. Methods: A search of the scientific articles published between 1979 and 2018 was carried out by using PubMed/MEDLINE, Google Scholar and ACS Publications. The relevant research papers published in recognized international journals and on-line journals in English were preferred, but the review articles of specific importance were also included, although non-English language citations were excluded. Collected articles were reviewed by title, abstract and text for relevance with preference to more recent publications. Results: Results of the literature search indicate that membrane interactivity is shared by various drugs that act on α- and β-adrenergic, muscarinic and nicotinic acetylcholine, γ-aminobutyric acid type A, N-methyl-D-aspartate, opioid and transient receptor potential vanilloid type-1 receptors. These receptor agonists and antagonists not only interact with receptor proteins but also would structure-specifically interact with membrane lipids to affect receptors by modifying the lipid bilayer environments surrounding them with the resultant conformational change of receptor proteins. Conclusion: The structure-specific membrane interaction is pharmacologically contributable to diverse effects of receptor-acting drugs.

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“…Their results indicated that these monoterpenoids are inserted into lipid bilayers to locate in the region between the choline polar group, the glycerol and the first atoms of the acyl chains. Tsuchiya and Mizogami [ 58 ] characterized the membrane effects of terpenoid phenols that increase the fluidity of neuro-mimetic membranes at 1–10 μM with the relative potency being thymol > carvacrol > eugenol as well as 50–200 μM bupivacaine and lidocaine. These phytochemicals penetrated into lipid bilayers with preference to the deeper hydrophobic region of membranes.…”

Section: Phytochemicals With the Local Anesthetic Activitymentioning

confidence: 99%

Anesthetic Agents of Plant Origin: A Review of Phytochemicals with Anesthetic Activity

Tsuchiya

2017

Molecules

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The majority of currently used anesthetic agents are derived from or associated with natural products, especially plants, as evidenced by cocaine that was isolated from coca (Erythroxylum coca, Erythroxylaceae) and became a prototype of modern local anesthetics and by thymol and eugenol contained in thyme (Thymus vulgaris, Lamiaceae) and clove (Syzygium aromaticum, Myrtaceae), respectively, both of which are structurally and mechanistically similar to intravenous phenolic anesthetics. This paper reviews different classes of phytochemicals with the anesthetic activity and their characteristic molecular structures that could be lead compounds for anesthetics and anesthesia-related drugs. Phytochemicals in research papers published between 1996 and 2016 were retrieved from the point of view of well-known modes of anesthetic action, that is, the mechanistic interactions with Na+ channels, γ-aminobutyric acid type A receptors, N-methyl-d-aspartate receptors and lipid membranes. The searched phytochemicals include terpenoids, alkaloids and flavonoids because they have been frequently reported to possess local anesthetic, general anesthetic, antinociceptive, analgesic or sedative property. Clinical applicability of phytochemicals to local and general anesthesia is discussed by referring to animal in vivo experiments and human pre-clinical trials. This review will give structural suggestions for novel anesthetic agents of plant origin.

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Comparative Interactions of Anesthetic Alkylphenols with Lipid Membranes

Cited by 10 publications

References 39 publications

Synthesis and Pharmacological Properties of Novel Esters Based on Monocyclic Terpenes and GABA

Synthesis and Pharmacological Properties of Novel Esters Based on Monocyclic Terpenes and GABA

Membrane Interactivity Shared by Receptor- Acting Drugs

Anesthetic Agents of Plant Origin: A Review of Phytochemicals with Anesthetic Activity

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