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Keywords = prottremine

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5 pages, 615 KB  
Short Note
(1R,2R,6S)-3-Methyl-6-(3-(4-phenylpiperidin-1-yl)prop-1-en-2-yl)cyclohex-3-ene-1,2-diol
by Alexandra V. Podturkina, Nikolai S. Li-Zhulanov, Tatyana V. Rybalova, Konstantin P. Volcho and Nariman F. Salakhutdinov
Molbank 2025, 2025(4), M2088; https://doi.org/10.3390/M2088 - 12 Nov 2025
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose primary manifestation is motor dysfunction. Previous research showed that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Prottremine) exhibits potent antiparkinsonian activity in animal models of PD, with an efficacy comparable to levodopa. Herein, we [...] Read more.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose primary manifestation is motor dysfunction. Previous research showed that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Prottremine) exhibits potent antiparkinsonian activity in animal models of PD, with an efficacy comparable to levodopa. Herein, we report the synthesis of a new Prottremine derivative, (1R,2R,6S)-3-methyl-6-(3-(4-phenylpiperidin-1-yl)prop-1-en-2-yl)cyclohex-3-ene-1,2-diol. The compound was fully characterized and its structure was confirmed through single-crystal X-ray diffraction analysis. Full article
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21 pages, 5047 KB  
Article
Inhibitory Activity of N- and S-Functionalized Monoterpene Diols Towards Monoamine Oxidases A and B
by Alexandra V. Podturkina, Oleg V. Ardashov, Yuliya V. Soldatova, Darya A. Poletaeva, Anastasiya V. Smolina, Ekaterina P. Vasyuchenko, Yuri V. Vyatkin, Nikolai S. Li-Zhulanov, Irina I. Faingold, Nariman F. Salakhutdinov and Konstantin P. Volcho
Int. J. Mol. Sci. 2025, 26(1), 97; https://doi.org/10.3390/ijms26010097 - 26 Dec 2024
Viewed by 1193
Abstract
Monoamine oxidase B (MAO-B) inhibitors are widely used as part of combination drug therapy for Parkinson’s disease. As demonstrated in both in vitro and in vivo experiments, the monoterpenoid Prottremine and some of its derivatives exhibit high antiparkinsonian activity. In this study, the [...] Read more.
Monoamine oxidase B (MAO-B) inhibitors are widely used as part of combination drug therapy for Parkinson’s disease. As demonstrated in both in vitro and in vivo experiments, the monoterpenoid Prottremine and some of its derivatives exhibit high antiparkinsonian activity. In this study, the inhibitory activity of Prottremine and its derivatives (including 14 new 9-N- and S-derivatives) against MAO-A and MAO-B enzymes has been investigated for the first time. Compounds containing fragments of substituted anilines have demonstrated the highest activity against MAO-A; for example, compound 28 had an IC50 of 178 ± 44 μM. A significant proportion of the compounds tested, including Prottremine, exhibited moderate inhibitory activity towards MAO-B, with the most active being the o-aminoacetophenone derivative, which had an IC50 of 95 ± 5 μM. A molecular docking method for studying murine MAO-A and -B enzymes was developed using AlphaFold2 (v2.3.2), with further improvements. For the MAO-B enzyme, a strong correlation was observed between the molecular docking data and the measured activity of the compounds, with the maximum binding affinity registered for the most active compound. It is conceivable that the antiparkinsonian activity of Prottremine and some of its derivatives may be partially mediated, among other mechanisms, by MAO-B enzyme inhibition. Full article
(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)
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17 pages, 1924 KB  
Article
Pharmacokinetics and Dose Proportionality Study of a Novel Antiparkinsonian Agent, a 1H-1,2,4-Triazol-3-ylthio-conjugate of Prottremine
by Daria S. Gorina, Anastasiya V. Lastovka, Artem D. Rogachev, Alexandra V. Podturkina, Alla V. Pavlova, Oleg V. Ardashov, Nikolai S. Li-Zhulanov, Tatyana G. Tolstikova, Konstantin P. Volcho and Nariman F. Salakhutdinov
Molecules 2024, 29(18), 4498; https://doi.org/10.3390/molecules29184498 - 22 Sep 2024
Viewed by 2091
Abstract
The novel antiparkinsonian agent PA-96 is the focus of our research. PA-96 supported the survival of cultured naïve dopamine neurons, alleviated motor deficits in MPTP and haloperidol-based mice models of Parkinson’s disease, and increased the density of tyrosine hydroxylase positive neurons and dopamine [...] Read more.
The novel antiparkinsonian agent PA-96 is the focus of our research. PA-96 supported the survival of cultured naïve dopamine neurons, alleviated motor deficits in MPTP and haloperidol-based mice models of Parkinson’s disease, and increased the density of tyrosine hydroxylase positive neurons and dopamine concentration in the midbrain of an MPTP-damaged brain. In this work, an HPLC–MS/MS method was developed and validated, and the pharmacokinetics of the agent was investigated in mice after a single or multiple oral administration (p.o.) and intravenous injection (i.v.) at various doses. The dose proportionality was also evaluated after a single p.o. administration of three ascending doses (1, 5, and 10 mg/kg) and a single i.v. injection of two doses (1 and 10 mg/kg); also, the bioavailability was estimated. The disproportionality of pharmacokinetic parameters could be explained by the saturation of active centres of enzymes or receptors binding the substance: at low doses, part of the compound is bound, leaving a small amount circulating in blood, and rapidly metabolised and/or bound too. The bioavailability of PA-96 was c.a. 7 and 35% for the doses of 5 and 10 mg/kg, correspondingly. Full article
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21 pages, 2165 KB  
Article
A New Stereoselective Approach to the Substitution of Allyl Hydroxy Group in para-Mentha-1,2-diol in the Search for New Antiparkinsonian Agents
by Alexandra V. Podturkina, Oleg V. Ardashov, Konstantin P. Volcho and Nariman F. Salakhutdinov
Molecules 2023, 28(21), 7303; https://doi.org/10.3390/molecules28217303 - 27 Oct 2023
Viewed by 1764
Abstract
Two approaches to the synthesis of para-menthene epoxide ((1S,5S,6R)-4) are developed. The first approach includes a reaction between chlorohydrin 7 and NaH in THF. The second involves the formation of epoxide in the [...] Read more.
Two approaches to the synthesis of para-menthene epoxide ((1S,5S,6R)-4) are developed. The first approach includes a reaction between chlorohydrin 7 and NaH in THF. The second involves the formation of epoxide in the reaction of corresponding diacetate 6 with sodium tert-butoxide. One possible mechanism of this reaction is proposed to explain unexpected outcomes in the regio- and stereospecificity of epoxide (1S,5S,6R)-4 formation. The epoxide ring in (1S,5S,6R)-4 is then opened by various S- and O-nucleophiles. This series of reactions allows for the stereoselective synthesis of diverse derivatives of the monoterpenoid Prottremine 1, a compound known for its antiparkinsonian activity, including promising antiparkinsonian properties. Full article
(This article belongs to the Special Issue Novel Natural and Derivative Products: Synthesis and Pharmacological Potential II)
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5 pages, 877 KB  
Short Note
(1R,2R,6S)-2(4-(4-Isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enol
by Alexandra V. Podturkina, Nikolai S. Li-Zhulanov, Konstantin P. Volcho and Nariman F. Salakhutdinov
Molbank 2023, 2023(1), M1546; https://doi.org/10.3390/M1546 - 12 Jan 2023
Cited by 1 | Viewed by 2285
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder mainly characterized by movement dysfunction. Earlier, it was found that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Prottremin) demonstrated antiparkinsonian activity in vivo on different animal models of PD. The paper presents synthesis of new [...] Read more.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder mainly characterized by movement dysfunction. Earlier, it was found that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Prottremin) demonstrated antiparkinsonian activity in vivo on different animal models of PD. The paper presents synthesis of new Prottremin derivative, (1R,2R,6S)-2(4-(4-isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enol. The derivative was obtained by epoxide ring opening reaction with 1-(4-isopropylbenzyl)piperazine. The product yield was 48% after purification. Full article
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21 pages, 5852 KB  
Article
A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo
by Anastasiia Kotliarova, Alexandra V. Podturkina, Alla V. Pavlova, Daria S. Gorina, Anastasiya V. Lastovka, Oleg V. Ardashov, Artem D. Rogachev, Arseniy E. Izyurov, Alla B. Arefieva, Alexander V. Kulikov, Tatyana G. Tolstikova, Konstantin P. Volcho, Nariman F. Salakhutdinov and Yulia Sidorova
Molecules 2022, 27(23), 8286; https://doi.org/10.3390/molecules27238286 - 28 Nov 2022
Cited by 8 | Viewed by 3558
Abstract
Parkinson’s disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression [...] Read more.
Parkinson’s disease (PD) is the most common age-related movement disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons. To date, PD treatment strategies are mostly based on dopamine replacement medicines, which can alleviate motor symptoms but do not slow down the progression of neurodegeneration. Thus, there is a need for disease-modifying PD therapies. The aim of this work was to evaluate the neuroprotective effects of the novel compound PA96 on dopamine neurons in vivo and in vitro, assess its ability to alleviate motor deficits in MPTP- and haloperidol-based PD models, as well as PK profile and BBB penetration. PA96 was synthesized from (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl) cyclohex-3-ene-1,2-diol (Prottremin) using the original three-step stereoselective procedure. We found that PA96: (1) supported the survival of cultured näive dopamine neurons; (2) supported the survival of MPP+-challenged dopamine neurons in vitro and in vivo; (3) had chemically appropriate properties (synthesis, solubility, etc.); (4) alleviated motor deficits in MPTP- and haloperidol-based models of PD; (5) penetrated the blood–brain barrier in vivo; and (6) was eliminated from the bloodstream relative rapidly. In conclusion, the present article demonstrates the identification of PA96 as a lead compound for the future development of this compound into a clinically used drug. Full article
(This article belongs to the Special Issue Novel Natural and Derivative Products: Synthesis and Pharmacological Potential)
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