Influence of the degree of unsaturation of the acyl side chain upon the interaction of analogues of 1-arachidonoylglycerol with monoacylglycerol lipase and fatty acid amide hydrolase

S Vandevoorde, B Saha, A Mahadevan, R K Razdan, R G Pertwee, B R Martin, C J Fowler

Research output: Contribution to journalArticle

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Abstract

Little is known as to the structural requirements of the acyl side chain for interaction of acylglycerols with monoacylglycerol lipase (MAGL), the enzyme chiefly responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain. In the present study, a series of twelve analogues of 1-AG (the more stable regioisomer of 2-AG) were investigated with respect to their ability to inhibit the metabolism of 2-oleoylglycerol by cytosolic and membrane-bound MAGL. In addition, the ability of the compounds to inhibit the hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) was investigated. For cytosolic MAGL, compounds with 20 carbon atoms in the acyl chain and 2-5 unsaturated bonds inhibited the hydrolysis of 2-oleoylglycerol with similar potencies (IC50 values in the range 5.1-8.2 mu M), whereas the two compounds with a single unsaturated bond were less potent (IC50 values 19 and 21 mu M). The fully saturated analogue 1-monoarachidin did not inhibit the enzyme, whereas the lower side chain analogues 1-monopalmitin and 1-monomyristin inhibited the enzyme with IC50 values of 12 and 32 mu M, respectively. The 22-carbon chain analogue of 1-AG was also potent (IC50 value 4.5 mu M). Introduction of an alpha-methyl group for the C20:4, C20:3, and C22:4 compounds did not affect potency in a consistent manner. For the FAAH and the membrane-bound MAGL, there was no obvious relationship between the degree of unsaturation of the acyl side chain and the ability to inhibit the enzymes. It is concluded that increasing the number of unsaturated bonds on the acyl side chain of 1-AG from 1 to 5 has little effect on the affinity of acylglycerols for cytosolic MAGL. (c) 2005 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)104-109
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume337
DOIs
Publication statusPublished - 2005

Keywords

  • 2-arachidonoylglycerol
  • anandamide
  • monoacylglycerol lipase
  • fatty acid amide hydrolase
  • CANNABINOID RECEPTOR-LIGAND
  • RAT-BRAIN
  • ANANDAMIDE AMIDOHYDROLASE
  • SUBSTRATE-SPECIFICITY
  • 2-ARACHIDONOYLGLYCEROL
  • INHIBITION
  • HYDROLYSIS
  • ENZYME
  • 2-ARACHIDONYLGLYCEROL
  • PURIFICATION

Cite this

Influence of the degree of unsaturation of the acyl side chain upon the interaction of analogues of 1-arachidonoylglycerol with monoacylglycerol lipase and fatty acid amide hydrolase. / Vandevoorde, S ; Saha, B ; Mahadevan, A ; Razdan, R K ; Pertwee, R G ; Martin, B R ; Fowler, C J .

In: Biochemical and Biophysical Research Communications, Vol. 337, 2005, p. 104-109.

Research output: Contribution to journalArticle

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abstract = "Little is known as to the structural requirements of the acyl side chain for interaction of acylglycerols with monoacylglycerol lipase (MAGL), the enzyme chiefly responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain. In the present study, a series of twelve analogues of 1-AG (the more stable regioisomer of 2-AG) were investigated with respect to their ability to inhibit the metabolism of 2-oleoylglycerol by cytosolic and membrane-bound MAGL. In addition, the ability of the compounds to inhibit the hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) was investigated. For cytosolic MAGL, compounds with 20 carbon atoms in the acyl chain and 2-5 unsaturated bonds inhibited the hydrolysis of 2-oleoylglycerol with similar potencies (IC50 values in the range 5.1-8.2 mu M), whereas the two compounds with a single unsaturated bond were less potent (IC50 values 19 and 21 mu M). The fully saturated analogue 1-monoarachidin did not inhibit the enzyme, whereas the lower side chain analogues 1-monopalmitin and 1-monomyristin inhibited the enzyme with IC50 values of 12 and 32 mu M, respectively. The 22-carbon chain analogue of 1-AG was also potent (IC50 value 4.5 mu M). Introduction of an alpha-methyl group for the C20:4, C20:3, and C22:4 compounds did not affect potency in a consistent manner. For the FAAH and the membrane-bound MAGL, there was no obvious relationship between the degree of unsaturation of the acyl side chain and the ability to inhibit the enzymes. It is concluded that increasing the number of unsaturated bonds on the acyl side chain of 1-AG from 1 to 5 has little effect on the affinity of acylglycerols for cytosolic MAGL. (c) 2005 Elsevier Inc. All rights reserved.",
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T1 - Influence of the degree of unsaturation of the acyl side chain upon the interaction of analogues of 1-arachidonoylglycerol with monoacylglycerol lipase and fatty acid amide hydrolase

AU - Vandevoorde, S

AU - Saha, B

AU - Mahadevan, A

AU - Razdan, R K

AU - Pertwee, R G

AU - Martin, B R

AU - Fowler, C J

PY - 2005

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N2 - Little is known as to the structural requirements of the acyl side chain for interaction of acylglycerols with monoacylglycerol lipase (MAGL), the enzyme chiefly responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain. In the present study, a series of twelve analogues of 1-AG (the more stable regioisomer of 2-AG) were investigated with respect to their ability to inhibit the metabolism of 2-oleoylglycerol by cytosolic and membrane-bound MAGL. In addition, the ability of the compounds to inhibit the hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) was investigated. For cytosolic MAGL, compounds with 20 carbon atoms in the acyl chain and 2-5 unsaturated bonds inhibited the hydrolysis of 2-oleoylglycerol with similar potencies (IC50 values in the range 5.1-8.2 mu M), whereas the two compounds with a single unsaturated bond were less potent (IC50 values 19 and 21 mu M). The fully saturated analogue 1-monoarachidin did not inhibit the enzyme, whereas the lower side chain analogues 1-monopalmitin and 1-monomyristin inhibited the enzyme with IC50 values of 12 and 32 mu M, respectively. The 22-carbon chain analogue of 1-AG was also potent (IC50 value 4.5 mu M). Introduction of an alpha-methyl group for the C20:4, C20:3, and C22:4 compounds did not affect potency in a consistent manner. For the FAAH and the membrane-bound MAGL, there was no obvious relationship between the degree of unsaturation of the acyl side chain and the ability to inhibit the enzymes. It is concluded that increasing the number of unsaturated bonds on the acyl side chain of 1-AG from 1 to 5 has little effect on the affinity of acylglycerols for cytosolic MAGL. (c) 2005 Elsevier Inc. All rights reserved.

AB - Little is known as to the structural requirements of the acyl side chain for interaction of acylglycerols with monoacylglycerol lipase (MAGL), the enzyme chiefly responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain. In the present study, a series of twelve analogues of 1-AG (the more stable regioisomer of 2-AG) were investigated with respect to their ability to inhibit the metabolism of 2-oleoylglycerol by cytosolic and membrane-bound MAGL. In addition, the ability of the compounds to inhibit the hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) was investigated. For cytosolic MAGL, compounds with 20 carbon atoms in the acyl chain and 2-5 unsaturated bonds inhibited the hydrolysis of 2-oleoylglycerol with similar potencies (IC50 values in the range 5.1-8.2 mu M), whereas the two compounds with a single unsaturated bond were less potent (IC50 values 19 and 21 mu M). The fully saturated analogue 1-monoarachidin did not inhibit the enzyme, whereas the lower side chain analogues 1-monopalmitin and 1-monomyristin inhibited the enzyme with IC50 values of 12 and 32 mu M, respectively. The 22-carbon chain analogue of 1-AG was also potent (IC50 value 4.5 mu M). Introduction of an alpha-methyl group for the C20:4, C20:3, and C22:4 compounds did not affect potency in a consistent manner. For the FAAH and the membrane-bound MAGL, there was no obvious relationship between the degree of unsaturation of the acyl side chain and the ability to inhibit the enzymes. It is concluded that increasing the number of unsaturated bonds on the acyl side chain of 1-AG from 1 to 5 has little effect on the affinity of acylglycerols for cytosolic MAGL. (c) 2005 Elsevier Inc. All rights reserved.

KW - 2-arachidonoylglycerol

KW - anandamide

KW - monoacylglycerol lipase

KW - fatty acid amide hydrolase

KW - CANNABINOID RECEPTOR-LIGAND

KW - RAT-BRAIN

KW - ANANDAMIDE AMIDOHYDROLASE

KW - SUBSTRATE-SPECIFICITY

KW - 2-ARACHIDONOYLGLYCEROL

KW - INHIBITION

KW - HYDROLYSIS

KW - ENZYME

KW - 2-ARACHIDONYLGLYCEROL

KW - PURIFICATION

U2 - 10.1016/j.bbrc.2005.09.015

DO - 10.1016/j.bbrc.2005.09.015

M3 - Article

VL - 337

SP - 104

EP - 109

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

ER -