Tat’yana Tolstikova

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.

Highly potent analgesic activity of monoterpene-derived (2S,4aR,8R,8aR)-2-aryl-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diols

New chiral heterocyclic compounds with a hexahydro-2H-chromene framework were synthesized by reactions of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol with aromatic aldehydes in the presence of montmorillonite clay. The analgesic activity of the compounds was studied in vivo. The majority of these compounds showed significant analgesic activity in the acetic acid-induced writhing test; the compounds containing one hydroxy and one methoxy substituents also showed analgesic activity in the hot-plate test. (2S,4aR,8R,8aR)-2-(3-Hydroxy-4-methoxyphenyl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diol was as effective as the diclofenac sodium reference taken in the same dose in both tests. It has low acute toxicity and is very promising for further development.

Synthesis and analgesic activity of new compounds combining azaadamantane and monoterpene moieties

Synthesis of new compounds that combine the diazaadamantane and monoterpenoid moieties was carried out based on the reaction between dimethylbispidinone and monoterpene-derived aldehydes. Investigation of the analgesic activity of the obtained products revealed that compound 5a synthesized from (−)-myrtenal had a higher efficacy compared with the reference drug, diclofenac sodium, in the acetic acid-induced writhing and hot plate tests. Compound 5a exhibits a low acute toxicity and does not cause damage to the gastric mucosa, and its analgesic effect is, at least partially, mediated by the cannabinoid system involving CB1 receptors.

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.

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.

Synthesis and analgesic activity of stereoisomers of 2-(3(4)-hydroxy-4(3)-methoxyphenyl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diols

Abstract2-(3(4)-Hydroxy-4(3)-methoxyphenyl)-4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diols were found recently to possess high analgesic activity and low acute toxicity. Stereoisomers of these compounds with high optical purity were synthesized from (+)- and (−)-α-pinenes for the first time in this work. The structure of (4S)-4b isomer was confirmed by the XRD data. Studies of analgesic activity of the resulting products demonstrated that neither the absolute configuration nor cis- or trans-arrangement of vicinal oxygen atoms plays a significant role in manifestation of analgesic effect by these isomers, while only (4S)-4b isomer, but not (4R)-4b demonstrated the analgesic effect.

Synthesis and analgesic activity of monoterpenoid-derived alkyl-substituted chiral hexahydro-2H-chromenes

A set of new 2-alkyl-substituted 4,7-dimethyl-3,4,4a,5,8,8a-hexahydro-2H-chromene-4,8-diols was obtained by reactions of monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol with aliphatic aldehydes in the presence of montmorillonite clay K10. Synthesized compounds were evaluated for their analgesic activity in vivo using the acetic acid-induced writhing test and the hot-plate test. Five compounds showed a significant analgesic activity in the acetic acid-induced writhing test; two of them also demonstrated analgesic activity in the hot-plate test. These compounds seem to be most promising for further development.

Synthesis and analgesic activity of amines combining diazaadamantane and monoterpene fragments

BACKGROUND It was found earlier that compounds combining diazaadamantane and monoterpene moieties possessed promising analgesic activity along with low acute toxicity and the lack of ulcerogenic activity. OBJECTIVE In this paper, new structural analogues of the most active compounds were synthesized and evaluated for their analgesic activity. METHODS Their structures were confirmed by various analytical methods, such as 1H and 13C NMR, HRMS. All of them were evaluated for analgesic activity at a dose of 20 mg/kg or less using acetic acid-induced writhing test and hot plate test. RESULTS Some compounds showed analgesic activity in acetic acid-induced writhing test. One of the synthesized compounds demonstrated high analgesic activity in both tests with 46% effect in acetic acid-induced writhing test and 89% effect in hot plate test. Both structural fragments of this compound did not possess any analgesic effect at a dose of 20 mg/kg. CONCLUSION Structure-activity relationships indicated that the most active compound combines fragments of (-)-myrtenal and 6-amino-5,7-dimethyl-1,3-diazaadamantane. Both parts of the molecule are important for demonstrating analgesic activity.