Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

Mikko J. Myllymaki; Heikki Kasnanen; Antti O. Kataja; Maija Lahtela-Kakkonen; Susanna M. Saario; Antti Poso; Ari M.P. Koskinen

doi:10.1016/j.ejmech.2009.05.012

Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

Mikko J. Myllymaki, Heikki Kasnanen, Antti O. Kataja, Maija Lahtela-Kakkonen, Susanna M. Saario, Antti Poso, Ari M.P. Koskinen

Research output: Contribution to journal › Article › Scientific › peer-review

19 Citations (Scopus)

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Abstract

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.

Original language	English
Pages (from-to)	4179-4191
Journal	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume	44
Issue number	10
DOIs	https://doi.org/10.1016/j.ejmech.2009.05.012
Publication status	Published - 2009
MoE publication type	A1 Journal article-refereed

Keywords

FAAH inhibitor
fatty acid amide hydrolase (FAAH)
carbamate
enantiomeric pair

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10.1016/j.ejmech.2009.05.012

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Myllymaki, M. J., Kasnanen, H., Kataja, A. O., Lahtela-Kakkonen, M., Saario, S. M., Poso, A., & Koskinen, A. M. P. (2009). Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 44(10), 4179-4191. https://doi.org/10.1016/j.ejmech.2009.05.012

Myllymaki, Mikko J. ; Kasnanen, Heikki ; Kataja, Antti O. ; Lahtela-Kakkonen, Maija ; Saario, Susanna M. ; Poso, Antti ; Koskinen, Ari M.P. / Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields. In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 2009 ; Vol. 44, No. 10. pp. 4179-4191.

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abstract = "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.",

keywords = "FAAH inhibitor, fatty acid amide hydrolase (FAAH), carbamate, enantiomeric pair",

author = "Myllymaki, {Mikko J.} and Heikki Kasnanen and Kataja, {Antti O.} and Maija Lahtela-Kakkonen and Saario, {Susanna M.} and Antti Poso and Koskinen, {Ari M.P.}",

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doi = "10.1016/j.ejmech.2009.05.012",

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Myllymaki, MJ, Kasnanen, H, Kataja, AO, Lahtela-Kakkonen, M, Saario, SM, Poso, A & Koskinen, AMP 2009, 'Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields', EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 44, no. 10, pp. 4179-4191. https://doi.org/10.1016/j.ejmech.2009.05.012

Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields. / Myllymaki, Mikko J.; Kasnanen, Heikki; Kataja, Antti O.; Lahtela-Kakkonen, Maija; Saario, Susanna M.; Poso, Antti; Koskinen, Ari M.P.

In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, Vol. 44, No. 10, 2009, p. 4179-4191.

Research output: Contribution to journal › Article › Scientific › peer-review

TY - JOUR

T1 - Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

AU - Myllymaki, Mikko J.

AU - Kasnanen, Heikki

AU - Kataja, Antti O.

AU - Lahtela-Kakkonen, Maija

AU - Saario, Susanna M.

AU - Poso, Antti

AU - Koskinen, Ari M.P.

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - FAAH inhibitor

KW - fatty acid amide hydrolase (FAAH)

KW - carbamate

KW - enantiomeric pair

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DO - 10.1016/j.ejmech.2009.05.012

M3 - Article

VL - 44

SP - 4179

EP - 4191

JO - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

SN - 0223-5234

IS - 10

ER -