ライフサイエンスコーパス: MAGL

1 MAGL inhibitors might be developed to treat conditions t

2 MAGL modulates hepatic injury via endocannabinoid and ei

3 MAGL(-)/(-) mice exhibited enhanced learning as shown by

4 MAGL-disrupted animals show neuroprotection in a parkins

5 Additionally, MAGL global knockout, but not cell type-specific knockou

6 noid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption

7 ogenicity-phenotypes that are reversed by an MAGL inhibitor.

8 essing the therapeutic potential of DAGL and MAGL inhibitors in pain, inflammation, degenerative dise

9 Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that wer

10 gly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a C

11 potency and selectivity toward both FAAH and MAGL.

12 ts suggest that both neuronal and astrocytic MAGL contribute to 2-AG clearance and prevent CB1 recept

13 synapses, while both neuronal and astrocytic MAGL significantly contributes to the termination of DSE

14 tive contribution of neuronal and astrocytic MAGL to the termination of DSE and DSI in Purkinje cells

15 We investigated whether blocking MAGL protects against inflammation and damage from hepat

16 enetic evidence that inactivation of 2-AG by MAGL determines the time course of eCB-mediated retrogra

17 ic evidence that the inactivation of 2-AG by MAGL determines the time course of the eCB-mediated retr

18 Reducing Abeta and neuroinflammation by MAGL inhibition was occluded by PPARgamma antagonism.

19 etrograde synaptic depression was rescued by MAGL inhibitor JZL184.

20 ulated miR-188-3p expression was restored by MAGL inhibition.

21 ertebrates (CB2 and DAGLbeta), or chordates (MAGL and COX2), or animals (DAGLalpha and CB1-like recep

22 Chronic MAGL blockade also caused physical dependence, impaired

23 subset of withdrawal signs, whereas complete MAGL inhibition elicits enhanced antiwithdrawal efficacy

24 This study reports a potent covalent MAGL inhibitor, SAR127303.

25 n contrast to the other previously described MAGL inhibitors, these compounds behave as reversible in

26 Also consistent with CB1 desensitization, MAGL-deficient mice do not show alterations in neuropath

27 presents a privileged template for designing MAGL inhibitors.

28 olds can be tuned for MAGL-selective or dual MAGL-FAAH inhibition by the attachment of an appropriate

29 pied by genetic disruption of Mgll (encoding MAGL).

30 bitor JZL184, as well as the novel dual FAAH-MAGL inhibitor SA-57, which is 100-fold more potent in i

31 rug discrimination behavior, where dual FAAH/MAGL blockade, but not disruption of either FAAH or MAGL

32 scribe a selective and efficacious dual FAAH/MAGL inhibitor, JZL195, and show that this agent exhibit

33 This was particularly intriguing for MAGL activity toward 15d-PGJ2-G whose hydrolysis rate ri

34 These scaffolds can be tuned for MAGL-selective or dual MAGL-FAAH inhibition by the attac

35 E-N41 and primary ARC neuronal cultures from MAGL(-/-) mice, respectively, and 4) associated with red

36 y because of the lack of compounds with good MAGL reversible inhibition properties.

37 Hepatocytes were the major source of hepatic MAGL activity and endocannabinoid and eicosanoid product

38 preferentially hydrolyzed PGD2-G, and human MAGL (hMAGL) robustly hydrolyzed all four.

39 and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG

40 These findings identify MAGL as a distinct metabolic node that couples endocanna

41 ction, and learning behavior were altered in MAGL knock-out mice.

42 pression in cerebellar slices was altered in MAGL knockout (MAGL(-/-)) mice.

43 induced depression of IPSCs was decreased in MAGL(-)/(-) mice.

44 d no significant effect on cerebellar DSE in MAGL(+/+) and (-/-) mice.

45 hese results suggest that 2-AG elevations in MAGL(-)/(-) mice cause tonic activation and partial dese

46 12 induced less depression of basal EPSCs in MAGL(-/-) mice than in MAGL(+/+) mice.

47 excitatory postsynaptic currents (EPSCs) in MAGL(-/-) mice but not in MAGL(+/+) mice.

48 Impairments in MAGL-dependent tumor growth are rescued by a high-fat di

49 The enhancement of TBS-LTP in MAGL(-)/(-) mice appears to be mediated by 2-AG-induced

50 nced basal IPSCs in CA1 pyramidal neurons in MAGL(-)/(-) mice, while the magnitude of DSI or CB(1) re

51 urrents (EPSCs) in MAGL(-/-) mice but not in MAGL(+/+) mice.

52 PF or mGluR1 agonist DHPG, was prolonged in MAGL(-/-) mice.

53 ion of basal EPSCs in MAGL(-/-) mice than in MAGL(+/+) mice.

54 These compounds are irreversible MAGL inhibitors that probably act by interacting with Cy

55 , these findings support the idea that joint MAGL and FAAH inhibition represents a promising approach

56 ebellar slices was altered in MAGL knockout (MAGL(-/-)) mice.

57 contribute to malignancy in cancers lacking MAGL activity.

58 Mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activit

59 Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are two enzy

60 es of inhibitors of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH).

61 that an increase in monoacylglycerol lipase (MAGL) drives tumorigenesis through the lipolytic release

62 sts in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglyce

63 etreatment with the monoacylglycerol lipase (MAGL) inhibitor MJN110 (which selectively elevates 2-AG)

64 Monoacylglycerol lipase (MAGL) inhibitors are considered potential therapeutic ag

65 g selective, potent monoacylglycerol lipase (MAGL) inhibitors.

66 how that the enzyme monoacylglycerol lipase (MAGL) is highly expressed in aggressive human cancer cel

67 Monoacylglycerol lipase (MAGL) is responsible for signal termination of 2-arachid

68 Monoacylglycerol lipase (MAGL) links these pathways, hydrolyzing the endocannabin

69 catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH) attenuates na

70 Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the end

71 ctive inhibitor for monoacylglycerol lipase (MAGL) that hydrolyzes 2-AG, induced a CB1 receptor-depen

72 inly carried out by monoacylglycerol lipase (MAGL), along with a small contribution by the alpha/beta

73 AG-degrading enzyme monoacylglycerol lipase (MAGL), and assessing the therapeutic potential of DAGL a

74 hydrolase (FAAH) or monoacylglycerol lipase (MAGL), enzymes that regulate the two major endocannabino

75 e hydrolase (FAAH), monoacylglycerol lipase (MAGL), N-acylethanolamine acid amidase (NAAA), or cycloo

76 ns of inhibitors of monoacylglycerol lipase (MAGL), the major degradative enzyme of the endocannabino

77 that inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that metabolizes the endocanna

78 ned inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocann

79 netic disruption of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocann

80 graded primarily by monoacylglycerol lipase (MAGL), which is expressed in neurons and astrocytes.

81 2-AG, inhibition of monoacylglycerol lipase (MAGL), which metabolizes 2-AG, facilitated the potentiat

82 olyzed primarily by monoacylglycerol lipase (MAGL).

83 he serine hydrolase monoacylglycerol lipase (MAGL).

84 ) is inactivated by monoacylglycerol lipase (MAGL).

85 olysed primarily by monoacylglycerol lipase (MAGL).

86 Many MAGL inhibitors are reported in literature; however, mos

87 We report that neuronal MAGL plays a predominant role in terminating DSE at clim

88 y anchoring point for the development of new MAGL inhibitors.

89 ges previous claims regarding the ability of MAGL to catalyze PG-G hydrolysis and extend the MAGL sub

90 ino acid residues in the catalytic cavity of MAGL, play important roles in determining the rate and t

91 hiocarbamate derivatives as a novel class of MAGL inhibitors.

92 se results indicate that genetic deletion of MAGL causes profound changes in eCB signaling, long-term

93 ptic depression and that genetic deletion of MAGL causes tonic activation and consequential desensiti

94 We show that genetic deletion of MAGL prolonged DSE at parallel fibre (PF) or climbing fi

95 Genetic deletion of MAGL selectively enhanced theta burst stimulation (TBS)-

96 A low-dose of MAGL inhibitors produces antidepressant effects on acute

97 In contrast, a high-dose of MAGL inhibitors produces pro- or antidepressant effects

98 ors for studying the endogenous functions of MAGL and FAAH.

99 In the hippocampus, in vivo inhibition of MAGL induces a CB1 cannabinoid receptor (CB1R)-dependent

100 ys242 was also found to impair inhibition of MAGL, especially that by fluorophosphonate derivatives (

101 by global and cell type-specific knockout of MAGL.

102 A lack of MAGL activity and subsequent long-term elevation of 2-AG

103 mpound that showed a reversible mechanism of MAGL inhibition (Ki = 8.6 muM), we started its structura

104 ng insights into the molecular mechanisms of MAGL-catalyzed hydrolysis of the primary endocannabinoid

105 Overexpression of MAGL in nonaggressive cancer cells recapitulates this fa

106 r investigation to evaluate the potential of MAGL inhibitors as antiepileptics.

107 ed to evaluate their inhibitory potential on MAGL activity as well as their selectivity over fatty ac

108 ockade, but not disruption of either FAAH or MAGL alone, produced THC-like responses that were revers

109 r combined, full FAAH inhibition and partial MAGL represents an optimal strategy to reduce opioid wit

110 owest: PTPN22, NAAA, TRPV1, TRPA1, NAPE-PLD, MAGL, PPARgamma, FAAH1, COX2, FAAH2, ABDH4, CB2, GPR55,

111 1-carbodithioate] (CK37), as the most potent MAGL inhibitor within this series (IC(50) = 154 nM).

112 ut as potent inhibitors of human recombinant MAGL (IC(50) (8) = 4.1 muM; IC(50) (30) = 2.4 muM), rat

113 The use of reversible MAGL inhibitors has been only partially investigated so

114 lore the therapeutic potential of reversible MAGL inhibitors.

115 zine-1-carbodithioate] (CK16) as a selective MAGL inhibitor.

116 and we developed a new potent and selective MAGL inhibitor (17b, Ki = 0.65 muM).

117 s of hepatic I/R in mice given the selective MAGL inhibitor JZL184, in Mgll(-/-) mice, fatty acid ami

118 Long and short MAGL isoforms shared a similar substrate profile, and hM

119 pound 51 over the supposed main off-targets, MAGL and COX, was found to be >900-fold.

120 100-fold more potent in inhibiting FAAH than MAGL, would prevent spontaneous withdrawal in morphine-d

121 We have recently discovered that MAGL and FAAH are both inhibited by carbamates bearing a

122 vide the first genetic in vivo evidence that MAGL is the major regulator of 2-AG levels and signaling

123 a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydrolysis in vivo.

124 We report that MAGL(-)/(-) mice exhibited prolonged depolarization-indu

125 ese findings highlight the central role that MAGL plays in endocannabinoid metabolism in vivo and rev

126 After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and pr

127 L to catalyze PG-G hydrolysis and extend the MAGL substrate profile beyond the classic monoacylglycer

128 ater molecule reproducing its H-bonds in the MAGL binding site, thus identifying a new key anchoring

129 ouse model with a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydro

130 e FAAH inhibitor PF-3845 and low-dose of the MAGL inhibitor JZL184, as well as the novel dual FAAH-MA

131 Systemic pretreatment with the MAGL inhibitor, MJN110, prevented the aversive effects o

132 is the normal behavioral response, and thus, MAGL inhibitors, which produce antidepressant effects in

133 eading to depressive-like behaviors, whereas MAGL inhibitor JZL184 produces antidepressant-like effec

134 Using knockout mice in which MAGL is deleted globally or selectively in neurons or as