{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T16:42:54Z","timestamp":1788799374222,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T00:00:00Z","timestamp":1669593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004569","name":"Ministry of Science and Higher Education, Russian Federation","doi-asserted-by":"publisher","award":["075-15-2020-777"],"award-info":[{"award-number":["075-15-2020-777"]}],"id":[{"id":"10.13039\/501100004569","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Helsinki","award":["075-15-2020-777"],"award-info":[{"award-number":["075-15-2020-777"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Parkinson\u2019s 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 n\u00e4ive 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\u2013brain 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.<\/jats:p>","DOI":"10.3390\/molecules27238286","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T07:38:49Z","timestamp":1669621129000},"page":"8286","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1071-9724","authenticated-orcid":false,"given":"Anastasiia","family":"Kotliarova","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia"},{"name":"Laboratory of Molecular Neuroscience, Institute of Biotechnology, HiLIFe, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra V.","family":"Podturkina","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alla V.","family":"Pavlova","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria S.","family":"Gorina","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia"},{"name":"Faculty of Natural Sciences, Novosibirsk State University, Pirogova, 2, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiya V.","family":"Lastovka","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia"},{"name":"Faculty of Natural Sciences, Novosibirsk State University, Pirogova, 2, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg V.","family":"Ardashov","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3338-8529","authenticated-orcid":false,"given":"Artem D.","family":"Rogachev","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia"},{"name":"V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, Pirogova, 2, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arseniy E.","family":"Izyurov","sequence":"additional","affiliation":[{"name":"Department of Genetic Collections of Neural Disorders, Federal Research Center Institute of Cytology and Genetic, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alla B.","family":"Arefieva","sequence":"additional","affiliation":[{"name":"Department of Genetic Collections of Neural Disorders, Federal Research Center Institute of Cytology and Genetic, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3816-6244","authenticated-orcid":false,"given":"Alexander V.","family":"Kulikov","sequence":"additional","affiliation":[{"name":"Department of Genetic Collections of Neural Disorders, Federal Research Center Institute of Cytology and Genetic, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana G.","family":"Tolstikova","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4083-9324","authenticated-orcid":false,"given":"Konstantin P.","family":"Volcho","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nariman F.","family":"Salakhutdinov","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8230-0530","authenticated-orcid":false,"given":"Yulia","family":"Sidorova","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuroscience, Institute of Biotechnology, HiLIFe, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.euroneuro.2011.08.008","article-title":"Cost of Disorders of the Brain in Europe 2010","volume":"21","author":"Gustavsson","year":"2011","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1136\/jnnp-2019-322338","article-title":"Parkinson\u2019s Disease: Etiopathogenesis and Treatment","volume":"91","author":"Jankovic","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1002\/mds.27115","article-title":"Past, Present, and Future of Parkinson\u2019s Disease: A Special Essay on the 200th Anniversary of the Shaking Palsy","volume":"32","author":"Obeso","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"114378","DOI":"10.1016\/j.ejmech.2022.114378","article-title":"Discovery of Small-Molecule Compounds and Natural Products against Parkinson\u2019s Disease: Pathological Mechanism and Structural Modification","volume":"237","author":"Zhong","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1007\/s00232-015-9778-9","article-title":"Permeability of the Blood-Brain Barrier: Molecular Mechanism of Transport of Drugs and Physiologically Important Compounds","volume":"248","author":"Fong","year":"2015","journal-title":"J. Membr. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"268","DOI":"10.2174\/1570159X16666180905094123","article-title":"Neuroregeneration in Parkinson\u2019s Disease: From Proteins to Small Molecules","volume":"17","author":"Sidorova","year":"2019","journal-title":"Curr. Neuropharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Prasad, E.M., and Hung, S.-Y. (2021). Current Therapies in Clinical Trials of Parkinson\u2019s Disease: A 2021 Update. Pharmaceuticals, 14.","DOI":"10.3390\/ph14080717"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1134\/S0012496610060074","article-title":"A Highly Effective Antiparkinsonian Drug of a New Structural Type","volume":"435","author":"Tolstikova","year":"2010","journal-title":"Dokl. Biol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3866","DOI":"10.1021\/jm2001579","article-title":"Highly Potent Activity of (1R,2R,6S)-3-Methyl-6-(Prop-1-En-2-Yl) Cyclohex-3-Ene-1,2-Diol in Animal Models of Parkinson\u2019s Disease","volume":"54","author":"Ardashov","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.ejphar.2017.09.022","article-title":"Evolution of Anti-Parkinsonian Activity of Monoterpenoid (1R,2R,6S)-3-Methyl-6-(Prop-1-En-2-Yl) Cyclohex-3-Ene-1,2-Diol in Various in Vivo Models","volume":"815","author":"Valdman","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/hlca.200790042","article-title":"Reactions of Allyl Alcohols of the Pinane Series and of Their Epoxides in the Presence of Montmorillonite Clay","volume":"90","author":"Ilyina","year":"2007","journal-title":"Helv. Chim. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"731","DOI":"10.2174\/1573406411309050013","article-title":"3-Methyl-6-(Prop-1-En-2-Yl) Cyclohex-3-Ene-1,2-Diol: The Importance of Functional Groups for Antiparkinsonian Activity","volume":"9","author":"Ardashov","year":"2013","journal-title":"Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1016\/j.bmc.2013.01.003","article-title":"Antiparkinsonian Activity of Some 9-N-, O-, S- and C-Derivatives of 3-Methyl-6-(Prop-1-En-2-Yl) Cyclohex-3-Ene-1,2-Diol","volume":"21","author":"Ardashov","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4337","DOI":"10.1021\/acschemneuro.9b00396","article-title":"A Novel Small Molecule Supports the Survival of Cultured Dopamine Neurons and May Restore the Dopaminergic Innervation of the Brain in the MPTP Mouse Model of Parkinson\u2019s Disease","volume":"10","author":"Ardashov","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"375","DOI":"10.2174\/157018011794839411","article-title":"Antiviral Activity of 3-Methyl-6-(Prop-1-En-2-Yl) Cyclohex-3-Ene-1,2-Diol and Its Derivatives Against Influenza A(H1N1)2009 Virus","volume":"8","author":"Ardashov","year":"2011","journal-title":"Lett. Drug Des. Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101752","DOI":"10.1016\/j.jchemneu.2020.101752","article-title":"Advancement in the Modelling and Therapeutics of Parkinson\u2019s Disease","volume":"104","author":"Rai","year":"2020","journal-title":"J. Chem. Neuroanat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e88","DOI":"10.1002\/cpns.88","article-title":"Back and to the Future: From Neurotoxin-Induced to Human Parkinson\u2019s Disease Models","volume":"91","author":"Airavaara","year":"2020","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/j.tips.2020.09.010","article-title":"Can Growth Factors Cure Parkinson\u2019s Disease?","volume":"41","author":"Sidorova","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1046\/j.1471-4159.2001.00183.x","article-title":"The Parkinsonian Toxin 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP): A Technical Review of Its Utility and Safety","volume":"76","author":"Przedborski","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/nprot.2006.342","article-title":"Protocol for the MPTP Mouse Model of Parkinson\u2019s Disease","volume":"2","author":"Przedborski","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/syn.20089","article-title":"Selective Alterations of Gene Expression in Mice Induced by MPTP","volume":"55","author":"Xu","year":"2005","journal-title":"Synapse"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115","DOI":"10.2478\/amma-2021-0017","article-title":"Beneficial Effects of Metformin on Haloperidol-Induced Motor Deficits in Rats. A Behavioral Assessment","volume":"67","author":"Gall","year":"2021","journal-title":"Acta Marisiensis Ser. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/S0028-3908(98)00215-9","article-title":"Inhibition of Mitochondrial Complex I by Haloperidol: The Role of Thiol Oxidation","volume":"38","author":"Balijepalli","year":"1999","journal-title":"Neuropharmacology"},{"key":"ref_24","first-page":"4327","article-title":"Anti-Angiogenic Activity of Annona Reticulata n-Hexane Seeds Extract: In Vivo Study","volume":"21","author":"Razzaq","year":"2021","journal-title":"Biochem. Cell. Arch."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s00441-020-03227-4","article-title":"Glial Cell Line-Derived Neurotrophic Factors (GFLs) and Small Molecules Targeting RET Receptor for the Treatment of Pain and Parkinson\u2019s Disease","volume":"382","author":"Mahato","year":"2020","journal-title":"Cell Tissue Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1002\/dneu.20760","article-title":"Novel CDNF\/MANF Family of Neurotrophic Factors","volume":"70","author":"Lindholm","year":"2010","journal-title":"Dev. Neurobiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"132","DOI":"10.2174\/9789815040678122100005","article-title":"Neurotrophic Factors to Combat Neurodegeneration","volume":"Volume 10","author":"Sidorova","year":"2022","journal-title":"Frontiers in Clinical Drug Research CNS and Neurological Disorders"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1002\/mds.21010","article-title":"Behavioral Models of Parkinson\u2019s Disease in Rodents: A New Look at an Old Problem","volume":"21","author":"Meredith","year":"2006","journal-title":"Mov. Disord."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.physbeh.2009.04.021","article-title":"Behavior, Neurotransmitters and Inflammation in Three Regimens of the MPTP Mouse Model of Parkinson\u2019s Disease","volume":"98","author":"Luchtman","year":"2009","journal-title":"Physiol. Behav."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S0896-6273(03)00568-3","article-title":"Parkinson\u2019s Disease: Mechanisms and Models","volume":"39","author":"Dauer","year":"2003","journal-title":"Neuron"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10189","DOI":"10.1073\/pnas.0403661101","article-title":"Altered Dopamine Signaling and MPTP Resistance in Mice Lacking the Parkinson\u2019s Disease-Associated GPR37\/Parkin-Associated Endothelin-like Receptor","volume":"101","author":"Marazziti","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","first-page":"339","article-title":"Axon Regeneration in the Peripheral and Central Nervous Systems","volume":"48","author":"Huebner","year":"2009","journal-title":"Results Probl. Cell Differ."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1134\/S0012496609060039","article-title":"(4S,5R,6R)-Para-Mentha-1,8-Dien-5,6-Diol Is a New Highly Effective Anticonvulsant Agent","volume":"429","author":"Tolstikova","year":"2009","journal-title":"Dokl. Biol. Sci."},{"key":"ref_34","unstructured":"(2022, September 29). Hazardous Drug Exposures in Health Care | NIOSH | CDC, Available online: https:\/\/www.cdc.gov\/niosh\/topics\/hazdrug\/default.html."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"365","DOI":"10.3389\/fphar.2017.00365","article-title":"A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat","volume":"8","author":"Sidorova","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"11861","DOI":"10.1038\/s41598-018-29988-1","article-title":"Two-Fold Elevation of Endogenous GDNF Levels in Mice Improves Motor Coordination without Causing Side-Effects","volume":"8","author":"Vilenius","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_37","first-page":"e3564","article-title":"Whole Animal Perfusion Fixation for Rodents","volume":"65","author":"Gage","year":"2012","journal-title":"JoVE J. Vis. Exp."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/jnr.23708","article-title":"Characterization of a New Low-Dose 6-Hydroxydopamine Model of Parkinson\u2019s Disease in Rat","volume":"94","author":"Penttinen","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1134\/S0026893320010148","article-title":"Effect of the C1473G Polymorphic Variant of the Tryptophan Hydroxylase 2 Gene and Photoperiod Length on the Dopamine System of the Mouse Brain","volume":"54","author":"Sinyakova","year":"2020","journal-title":"Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.cmpb.2010.01.007","article-title":"PKSolver: An Add-in Program for Pharmacokinetic and Pharmacodynamic Data Analysis in Microsoft Excel","volume":"99","author":"Zhang","year":"2010","journal-title":"Comput. Methods Programs Biomed."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/23\/8286\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:28:24Z","timestamp":1760146104000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/23\/8286"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,28]]},"references-count":40,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["molecules27238286"],"URL":"https:\/\/doi.org\/10.3390\/molecules27238286","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,28]]}}}