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.

Synthesis and evaluation of antitumor, anti-inflammatory and analgesic activity of novel deoxycholic acid derivatives bearing aryl- or hetarylsulfanyl moieties at the C-3 position.

Novel deoxycholic acid (DCA) derivatives were stereoselectively synthesised with -OH and -CH2SR moieties at the C-3 position, where R was a substituted aryl [2-aminophenyl (8) or 4-chlorophenyl (9)] or hetaryl [1-methylimidazolyl (5), 1,2,4-triazolyl (6), 5-amino-1,3,4-thiadiazolyl (7), pyridinyl (10) or pyrimidinyl (11)]. These compounds were prepared in good yields from the C-3ß-epoxy derivative 2 in the epoxide ring-opening reaction by S-nucleophiles. These derivatives were evaluated for their in vitro anti-proliferation activity in a panel of tumor cell lines. Data showed that: (i) heterocycle-containing derivatives displayed higher cytotoxicity profiles than the parent molecule; (ii) heterocyclic substituents were more preferable than aryl moieties for enhancing anti-proliferation activity; (iii) the sensitivity of tumor cell lines to analysed compounds decreased in the following order: HuTu-80 (duodenal carcinoma)>KB-3-1 (cervical carcinoma)>HepG2 (hepatocellular carcinoma)>MH-22a (hepatoma); (iv) compounds 5, 6 and 11 exhibited a high cytotoxic selectivity index (HuTu-80: SI>7.7, 38.5 and 12.0, respectively). Compounds 2 and 6-8 markedly inhibited NO synthesis by interferon γ-induced macrophages. Screening for anti-inflammatory activity of these derivatives in vivo showed their high potency on histamine- (5, 10) and formalin- (2, 10, 11) induced paw edema models.

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.

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.

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.

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.