Cystatins A and C were both shown to inhibit cathepsin B by a two-step mechanism, involving an initial weak interaction followed by a conformational change. Disruption of the major salt bridge anchoring the occluding loop of cathepsin B to the main body of the enzyme by mutation of His110 to Ala converted the binding to an apparent one-step reaction. The second step of cystatin binding to cathepsin B must therefore be due to the inhibitor having to alter the conformation of the enzyme by displacing the occluding loop to allow a tight complex to be formed. Cystatin A was appreciably less effective in displacing the loop than cystatin C, resulting in a considerably lower overall inhibition rate constant. ß

(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.

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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.

We previously showed that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2yl)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 choose epoxide 4, which potently restored locomotor activity in MPTP-treated mice and penetrated the BBB with high efficacy, to further explore the potential mechanism of action. Epoxide 4 was found to robustly promote the survival of cultured dopamine neurons, protect dopamine neurons from toxin-induced degeneration and trigger the mitogen-activated protein kinase (MAPK) signaling cascade in cells of neuronal 2 origin. Meanwhile, neither survival-promoting effect nor MAPK activation was observed in nonneuronal cells treated with epoxide 4. In the MPTP mice model of Parkinson's disease, compound 4 increased the density of fibers expressing the key enzyme of dopamine synthesis, tyrosine hydroxylase. Taken together, these data indicate that epoxide 4 can be a promising compound for further development not only as symptomatic treatment but also as a disease-modifying drug to treat Parkinson's disease.

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