Browsing by Author "Saario, Susanna M."

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    a-methylated derivatives of 2-arachidonyl glycerol: Synthesis, CB1 receptor activity and enzymatic stability
    (2006) Parkkari, Teija; Koskinen, Ari M.P.; Myllymäki, Mikko; Savinainen, Juha R.; Saario, Susanna M.; Castillo-Melendez, Joel A.; Laitinen, Jarmo T.; Nevalainen, Tapio; Järvinen, Tomi; Department of Chemistry
    a-Methylated analogues of the endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), were synthesized aiming to the improved enzymatic stability of 2-AG. In addition, the CB1 activity properties of fluoro derivatives of 2-AG were studied. The CB1 receptor activity was determined by the [35S]GTPcS binding assay, and the enzymatic stability of a-methylated analogues was determined in rat cerebellar membranes. The results indicate that even if the a-methylated 2-AG derivatives are slightly weaker CB1 receptor agonists than 2-AG, they are clearly more stable than 2-AG. In addition, the results showed that the replacement of the hydroxyl group(s) of 2-AG by fluorine does not improve the CB1 activity of 2-AG.
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    Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields
    (2009) Myllymaki, Mikko J.; Kasnanen, Heikki; Kataja, Antti O.; Lahtela-Kakkonen, Maija; Saario, Susanna M.; Poso, Antti; Koskinen, Ari M.P.; Department of Chemistry
    Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are the main enzymes responsible for the hydrolysis of endogenous cannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. Phenyl alkylcarbamates are FAAH inhibitors with anxiolytic and analgesic activities in vivo. Herein we present for the first time the synthesis and biological evaluation of a series of chiral 3-(2-oxazoline)-phenyl N-alkylcarbamates as FAAH inhibitors. Furthermore, the structural background of chirality on the FAAH inhibition is explored by analyzing the protein–ligand interactions. Remarkably, 10-fold difference in potency was observed for (R)- and (S)-derivatives of 3-(5-methyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (6a vs. 6b). Molecular modelling indicated an important interaction between the oxazoline nitrogen and FAAH active site.
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    Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors
    (2007) Myllymäki, Mikko J.; Saario, Susanna M.; Kataja, Antti O.; Castillo-Melendez, Joel A.; Nevalainen, Tapio; Juvonen, Risto O.; Järvinen, Tomi; Koskinen, Ari M.P.; Department of Chemistry
    Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydrolysis of the endocannabinoid N-arachidonoylethanolamide to arachidonic acid and ethanolamine. FAAH also hydrolyzes another endocannabinoid, 2-arachidonoylglycerol (2-AG). However, 2-AG has been assumed to be hydrolyzed mainly by monoacylglycerol lipase (MAGL) or a MAGL-like enzyme. Inhibition of FAAH or MAGL activity might lead to beneficial effects in many physiological disorders such as pain, inflammation, and anxiety due to increased endocannabinoid-induced activation of cannabinoid receptors CB1 and CB2. In the present study, a total of 34 novel compounds were designed, synthesized, characterized, and tested against FAAH and MAGL-like enzyme activity. Altogether, 16 compounds were found to inhibit FAAH with half-maximal inhibition concentrations (IC50) between 28 and 380 nM. All the active compounds belong to the structural family of carbamates. Compounds 14 and 18 were found to be the most potent FAAH inhibitors, which may serve as lead structures for novel FAAH inhibitors.
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    The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors
    (2009) Minkkila, Anna; Myllymaki, Mikko J.; Saario, Susanna M.; Castillo-Melendez, Joel A.; Koskinen, Ari M.P.; Fowler, Christopher J.; Leppanen, Jukka; Nevalainen, Tapio; Department of Chemistry
    A series of para-substituted phenolic N-alkyl carbamates were evaluated for their FAAH and MGL inhibitory activities. The compounds were generally selective for FAAH, with IC50 values in the nM range, whereas inhibition of MGL required concentrations three orders of magnitude higher. The most potent compounds, dodecylcarbamic acid 4-(4,5-dihydrothiazol-2-yl)phenyl (12) and 4-(1,2,3-thiadiazol-4-yl)phenyl (26) esters, inhibited FAAH and MGL with IC50 values at the low-nanomolar (IC50s; 0.0063 and 0.012 mM) and the low-micromolar ranges (IC50s; 2.1 and 1.0 mM), respectively. Compound 26 also inhibited both FAAH-dependent AEA uptake and AEA hydrolysis (IC50; 0.082 mM) by intact RBL2H3 cells, and could also reduce 2-AG hydrolysis by these cells at concentrations 0.030 mM.