A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo

A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo Full article

Journal

Molecules
, E-ISSN: 1420-3049

Output data

Year: 2022, Volume: 27, Number: 23, Article number : 8286, Pages count : 21 DOI: 10.3390/molecules27238286

Tags

Parkinson’s disease; MPTP; small molecules; dopamine neurons; tyrosine hydroxylase; Prottremin; epoxydiol; drug development; medicinal chemistry; neurodegeneration

Authors

Kotliarova Anastasiia ^1,2 , Podturkina Alexandra V. ¹ , Pavlova Alla V. ¹ , Gorina Daria S. ^1,3 , Lastovka Anastasiya V. ^1,3 , Ardashov Oleg V. ¹ , Rogachev Artem D. ^1,4 , Izyurov Arseniy E. ⁵ , Arefieva Alla B. ⁵ , Kulikov Alexander V. ⁵ , Tolstikova Tatyana G. ¹ , Volcho Konstantin P. ¹ , Salakhutdinov Nariman F. ¹ , Sidorova Yulia ²

Affiliations

1	Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia
2	Laboratory of Molecular Neuroscience, Institute of Biotechnology, HiLIFe, Viikinkaari 5D, University of Helsinki, 00014 Helsinki, Finland
3	Faculty of Natural Sciences, Novosibirsk State University, Pirogova, 2, 630090 Novosibirsk, Russia
4	V. Zelman Institute for Medicine and Psychology, Novosibirsk State University, Pirogova, 2, 630090 Novosibirsk, Russia
5	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

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.

Kotliarova A. , Podturkina A.V. , Pavlova A.V. , Gorina D.S. , Lastovka A.V. , Ardashov O.V. , Rogachev A.D. , Izyurov A.E. , Arefieva A.B. , Kulikov A.V. , Tolstikova T.G. , Volcho K.P. , Salakhutdinov N.F. , Sidorova Y.
A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo
Molecules. 2022. V.27. N23. 8286 :1-21. DOI: 10.3390/molecules27238286 WOS Scopus РИНЦ

Submitted:	Oct 21, 2022
Accepted:	Nov 22, 2022
Published online:	Nov 28, 2022

Web of science	WOS:000897422400001
Scopus	2-s2.0-85143623898
Elibrary	58579955
OpenAlex	W4310177740