A New Stereoselective Approach to the Substitution of Allyl Hydroxy Group in para-Mentha-1,2-diol in the Search for New Antiparkinsonian Agents.

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.

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

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.

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.

Earlier it was found, that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (1) possess high antiparkinsonian activity. The N-, O-, S- and C-derivatives at the C-9 position of diol 1 were synthesized in this work. The antiparkinsonian activity of these compounds was studied in MPTP mice models. As a rule, the introduction of substituents containing nitrogen atoms at the C-9 position led to a considerable decrease or loss of antiparkinsonian activity. A derivative of 2-aminoadamantane 8 significantly decreased the locomotor activity time, thus enhancing the symptoms of the parkinsonian syndrome. However the introduction of butyl or propylthio substituents at the C-9 position of diol 1 did not diminish the antiparkinsonian activity comparing to parent compound. This information is important when choosing a route for immobilization of compound 1 to find possible targets.

MPTP-Treated Zebrafish Recapitulate 'Late-Stage' Parkinson's-like Cognitive Decline.

The zebrafish is a promising model species in biomedical research, including neurotoxicology and neuroactive drug screening. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes degeneration of dopaminergic neurons and is commonly used to model Parkinson's disease (PD) in laboratory animals, including zebrafish. However, cognitive phenotypes in MPTP-evoked experimental PD models remain poorly understood. Here, we established an LD50 (292 mg/kg) for intraperitoneal MPTP administration in adult zebrafish, and report impaired spatial working memory (poorer spontaneous alternation in the Y-maze) in a PD model utilizing fish treated with 200 µg of this agent. In addition to conventional behavioral analyses, we also employed artificial intelligence (AI)-based approaches to independently and without bias characterize MPTP effects on zebrafish behavior during the Y-maze test. These analyses yielded a distinct cluster for 200-µg MPTP (vs. other) groups, suggesting that high-dose MPTP produced distinct, computationally detectable patterns of zebrafish swimming. Collectively, these findings support MPTP treatment in adult zebrafish as a late-stage experimental PD model with overt cognitive phenotypes.

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's Disease.

We previously showed that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 alleviates motor manifestations of Parkinson's disease in animal models. In the present study, we designed and synthesized monoepoxides of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 and evaluated their biological activity in the MPTP mouse model of Parkinson's disease. We also assessed the ability of these compounds to penetrate the blood-brain barrier (BBB). According to these data, we chose epoxide 4, which potently restored the locomotor activity in MPTP-treated mice and efficiently penetrated the BBB, to further explore its potential mechanism of action. Epoxide 4 was found to robustly promote the survival of cultured dopamine neurons, protect dopamine neurons against toxin-induced degeneration, and trigger the mitogen-activated protein kinase (MAPK) signaling cascade in cells of neuronal origin. Meanwhile, neither the survival-promoting effect nor MAPK activation was observed in non-neuronal cells treated with epoxide 4. In the MPTP mouse model of Parkinson's disease, compound 4 increased the density of dopamine neuron fibers in the striatum, which can highlight its potential to stimulate striatal reinnervation and thus halt disease progression. Taken together, these data indicate that epoxide 4 can be a promising compound for further development, not only as a symptomatic but also as a neuroprotective and neurorestorative drug for Parkinson's disease.

3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol: the importance of functional groups for antiparkinsonian activity.

Compounds with different sets of three of the four functional groups of (1R,2R,6S)-3-methyl-6-(prop-1-en-2- yl)cyclohex-3-ene-1,2-diol 1 possessing high antiparkinsonian activity were synthesized. The synthesized compounds were tested for the antiparkinsonian activity in vivo on a mouse model with MPTP neurotoxin. A pronounced antiparkinsonian effect of 1 can only be achieved if it contains all the four functional groups (two hydroxy groups and two double bonds). The 2-hydroxy group or the 3,4-double bond is not required for stimulating the exploratory activity of the animals.

Selective Preparation of trans-Carveol over Ceria Supported Mesoporous Materials MCM-41 and SBA-15.

Ce-modified mesoporous silica materials MCM-41 and SBA-15, namely 32 wt % Ce-Si-MCM-41, 16 wt % Ce-H-MCM-41 and 20 wt % Ce-Si-SBA-15, were prepared, characterized and studied in the selective preparation of trans-carveol by α-pinene oxide isomerization. The characterizations of these catalysts were performed using scanning electron microscopy, X-ray photoelectron spectroscopy, nitrogen adsorption and FTIR pyridine adsorption. Selective preparation of trans-carveol was carried out in the liquid phase in a batch reactor. The activity and the selectivity of catalyst were observed to be influenced by their acidity, basicity and morphology of the mesoporous materials. The formation of trans-carveol is moreover strongly influenced by the basicity of the used solvent and in order to achieve high yields of this desired alcohol it is necessary to use polar basic solvent.

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's disease.

(1R,2R,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol 1 possesses potent antiparkinsonian activity in both MPTP and haloperidol animal models. The use of compound 1 resulted in nearly full recovery of the locomotor and exploratory activities and was as effective as the comparator agent (levodopa). All eight stereoisomers of compound 1 have been synthesized and the influence of the absolute configuration on the antiparkinsonian activity of compound 1 was shown.