- The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors
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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 μM) and the low-micromolar ranges (IC50s; 2.1 and 1.0 μM), respectively. Compound 26 also inhibited both FAAH-dependent AEA uptake and AEA hydrolysis (IC50; 0.082 μM) by intact RBL2H3 cells, and could also reduce 2-AG hydrolysis by these cells at concentrations ≥0.030 μM.
- Minkkilae, Anna,Myllymaeki, Mikko J.,Saario, Susanna M.,Castillo-Melendez, Joel A.,Koskinen, Ari M.P.,Fowler, Christopher J.,Leppaenen, Jukka,Nevalainen, Tapio
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experimental part
p. 2994 - 3008
(2009/10/10)
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- Ortho effects and cross interaction correlations for the mechanisms of cholesterol esterase inhibition by aryl carbamates
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Ortho-substituted phenyl-N-butyl carbamates (1-11) were synthesized to evaluate the inhibition mechanisms of porcine pancreatic cholesterol esterase. All carbamate inhibitors act as the active site-directed pseudo substrate inhibitors of the enzymes. The logarithms of dissociation constant (K i), carbamylation constant (k2) and bimolecular inhibition constant (ki) multiply linearly correlate with the Hammett substituent constant (σ), the Taft-Kutter-Hansch ortho steric constant (Es), and the Swan-Lupton-Hansch ortho polar constant (F). For the -log Ki, log k2 and log ki correlations, the reaction constant for ordinary polar effect (ρ), the intensity factor to ortho steric constant (δ) and the intensity factor to ortho polar constant (f) are 0.7, -0.07, and 0.5; 0.5, 0.04 and -0.5; and 1.1, -0.03 and 0.0, respectively. The cross interaction reaction constant (ρXR) for the -log ki-, log k2- and log ki-σ- ασ*-ασσ* correlations are 3, -2, and 1, respectively. The Ki step may be composed of the following two steps: (1) protonation of carbamates 1-11 and (2) the pseudo-trans to pseudo-cis conformation change of protonated carbamates 1-11 due to a large ρXR value of 3 and formation of the enzyme-protonated carbamates 1-11 tetrahedral intermediate. The k2 step involves departure of the leaving group, which is protonated by the active site histidine of the enzyme, from the tetrahedral intermediate to solution and formation of the carbamyl enzyme. Moreover, the distances between the carbamate and phenyl groups in all transition states of inhibition reactions are relatively short owing to large |ρXR| values. The Ki step shows little ortho steric enhancement effect; moreover, the k2 step shows little ortho steric inhibition effect. Copyright
- Lin, Gialih,Liu, Yu-Chen,Wu, Yon-Gi,Lee, Yu-Ru
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p. 707 - 714
(2007/10/03)
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- Structure-reactivity relationships as probes for the inhibition mechanism of cholesterol esterase by aryl carbamates. I. Steady-state kinetics
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For substituted phenyl-N-butyl carbamates (1) and 4-nitrophenyl-N-substituted carbamates (2), linear relationships between values of NH proton chemical shift (δNH), pKa, and logk[OH] and Hammett substituent constant (σ) or Taft subst
- Lin, Gialih,Lai, Cheng-Yue,Liao, Wei-Cheng,Kuo, Bing-Hong,Lu, Chun-Ping
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p. 489 - 500
(2007/10/03)
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- Molecular recognition by acetylcholinesterase at the peripheral anionic site: Structure-activity relationships for inhibitions by aryl carbamates
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Substituted phenyl-N-butyl carbamates (1-9Figure 2Chemical structures of carbamates 1-9 and edrophonium.) are potent irreversible inhibitors of Electrophorus electricus acetylcholinesterase. Carbamates 1-9 act as the peripheral anionic site-directed irrev
- Lin, Gialih,Lai, Cheng-Yue,Liao, Wei-Cheng
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p. 2683 - 2689
(2007/10/03)
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- Linear free energy relationships of the inhibition of pancreatic cholesterol esterase by 4-nitrophenyl-N-alkylcarbamate
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4-Nitrophenyl-N-alkylcarbamates (1) as active site-directed irreversible inhibitors of pancreatic cholesterol esterase are investigated for values of the dissociation constant (K(i)), the carbamylation constant (k2), and the bimolecular rate co
- Lin, Gialih,Lai, Cheng-Yue
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p. 193 - 196
(2007/10/02)
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- Hammett Analysis of the Inhibition of Pancreatic Cholesterol Esterase by Substituted Phenyl-N-Butylcarbamate
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Substituted phenyl-N-butylcarbamates (1) as active site-directed irreversible inhibitors of pancreatic cholesterol esterase are investigated for values of the dissociation constant (KI), the carbamylation constant (k2), and the bimol
- Lin, Gialih,Lai, Cheng-Yue
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p. 6117 - 6120
(2007/10/02)
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- Aminolysis of cyclic carbamate analogs of carboxybiotin; metallic catalysis and modelling of carboxytransferase
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Aminolysis of carbamic esters, a model of the intermediate carboxybiotin in enzymatic carboxylations was studied in organic medium in the presence of a divalent cation. This study establishes electrostatic catalysis of aminolysis, the rate determining step of which is the collapse of the tetrahedral intermediate principally by carbon-nitrogen bond breaking. The results also account for the role of the divalent cation present in the carboxytransferase subunit of carboxylases.
- Botella,Klaebe,Perie,Monnier
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p. 5111 - 5122
(2007/10/02)
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