ライフサイエンスコーパス: MAGL

1 MAGL expression is increased in invasive tumors, furnish

2 MAGL inhibition provides therapeutic opportunities but c

3 MAGL inhibitors might be developed to treat conditions t

4 MAGL modulates hepatic injury via endocannabinoid and ei

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

6 MAGL-disrupted animals show neuroprotection in a parkins

7 The availability of a MAGL-specific positron emission tomography (PET) ligand

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

9 discuss biological factors that could affect MAGL inhibitor efficacy.

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

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

12 ial as a new class of therapeutic agents and MAGL could play a role in pancreatic cancer.

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

14 mation primes CB1Rs for desensitization, and MAGL degradation of 2-AG protects CB1Rs from desensitiza

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

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

17 potency and selectivity toward both FAAH and MAGL.

18 FASN and MAGL are enzymes that generate cellular fatty acid pools

19 Here, we show that the abilities of FASN and MAGL to promote nuclear receptor activation and PCa meta

20 Since FABP5, FASN, and MAGL have been independently implicated in PCa progressi

21 poxide hydrolase, sepiapterin reductase, and MAGL/FAAH, have also been targeted to develop novel anal

22 images of (R)-[(18)F]YH134 in wild-type and MAGL knockout mice demonstrated its high specificity and

23 play between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic op

24 ity relationship (SAR) of aryl sulfoxides as MAGL inhibitors that led to the identification of LEI-51

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

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

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

28 est that the class of benzylpiperidine-based MAGL inhibitors have potential as a new class of therape

29 Here, a new class of benzylpiperidine-based MAGL inhibitors was synthesized, leading to the identifi

30 eries of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays.

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

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

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

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

35 etrograde synaptic depression was rescued by MAGL inhibitor JZL184.

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

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

38 Chronic MAGL blockade also caused physical dependence, impaired

39 We find that chronic MAGL treatment stably facilitates goal seeking and DA en

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

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

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

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

44 presents a privileged template for designing MAGL inhibitors.

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

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

47 hesized in high yield and labeled endogenous MAGL in live cells.

48 ne was applied to the labeling of endogenous MAGL in live cells.

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

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

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

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

53 lity and permeability, picomolar potency for MAGL across various species, and high cell selectivity a

54 A covalent probe for MAGL incorporating 6-methyltetrazinyl functionality was

55 GL inhibitor (IC(50) = 80 nM), selective for MAGL over the other main components of the endocannabino

56 5v was identified as selective for MAGL when compared with other serine hydrolases.

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

58 substrate revealed an IC(50) of 15.8 uM for MAGL inhibition using BCP.

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

60 emonstrated beneficial effects deriving from MAGL inhibition for neurodegenerative diseases, inflamma

61 ce in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid

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

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

64 replacement enabled the combination of high MAGL potency with favorable ADME properties.

65 Regions with high MAGL expression, and therefore with potentially physiolo

66 brain tissue, such that regions with higher MAGL expression (but not fatty-acid amide hydrolase or F

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

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

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

70 ith favorable kinetic properties for imaging MAGL in rodent brain.

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

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

73 vivo studies in mice, showing a decrease in MAGL activity and increased 2-arachidonoyl-sn-glycerol l

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

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

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

77 12 induced less depression of basal EPSCs in MAGL(-/-) mice than in MAGL(+/+) mice.

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

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

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

81 eas the radioactive signal was negligible in MAGL knockout mouse brain slices.

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

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

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

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

86 s compared with vehicle controls, indicating MAGL enzyme inhibition.

87 These data showed that BCP inhibits MAGL activity in vitro and in vivo, causing 2-AG levels

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

89 ion of the potent and selective irreversible MAGL inhibitor 7 (PF-06809247) as a suitable radioligand

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

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

92 d a reduced formation of the isotope-labeled MAGL product 2-AG-d8 as compared with vehicle controls,

93 contribute to malignancy in cancers lacking MAGL activity.

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

95 Monoacylglycerol lipase (MAGL) activity was evaluated in vitro as well as ex vivo

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

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

98 DSI) was limited by monoacylglycerol lipase (MAGL) but not by fatty acid amide hydrolase.

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

100 onal differences in monoacylglycerol lipase (MAGL) expression in postmortem brain tissue, such that r

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

102 ith a low dose of a monoacylglycerol lipase (MAGL) inhibitor facilitates motivation and DA signaling

103 egradation with the monoacylglycerol lipase (MAGL) inhibitor JZL184 during inflammation results in th

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

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

106 w potent, selective monoacylglycerol lipase (MAGL) inhibitors based on the azetidin-2-one scaffold ((

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

108 Monoacylglycerol lipase (MAGL) is a hydrolase involved in lipid metabolism that c

109 Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of the

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

111 Monoacylglycerol lipase (MAGL) is one of the key enzymes in the endocannabinoid s

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

113 Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arac

114 Monoacylglycerol lipase (MAGL) is the enzyme responsible for the metabolism of 2-

115 Monoacylglycerol lipase (MAGL) is the key enzyme for the hydrolysis of endocannab

116 Monoacylglycerol lipase (MAGL) is the pivotal catabolic enzyme responsible for si

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

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

119 Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (

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

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

122 ed on inhibition of monoacylglycerol lipase (MAGL) to enhance signaling of the most abundant and effi

123 etrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was app

124 Inhibition of monoacylglycerol lipase (MAGL) with JZL184 increases the levels of the endocannab

125 Monoacylglycerol lipase (MAGL), a serine hydrolase extensively expressed througho

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

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

128 s catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental a

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

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

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

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

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

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

135 rget MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity o

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

137 2-AG, inhibition of monoacylglycerol lipase (MAGL), which metabolizes 2-AG, facilitated the potentiat

138 olysed primarily by monoacylglycerol lipase (MAGL).

139 olyzed primarily by monoacylglycerol lipase (MAGL).

140 he serine hydrolase monoacylglycerol lipase (MAGL).

141 tracer for imaging monoacylglycerol lipase (MAGL).

142 ynthase (FASN), and monoacylglycerol lipase (MAGL).

143 ) is inactivated by monoacylglycerol lipase (MAGL).

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

145 Methods: MAGL knockout and wild-type mice were used to evaluate (

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

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

148 These results suggest that the new MAGL inhibitors have therapeutic potential for different

149 In the quest for novel MAGL inhibitors, a focused screening approach on a Roche

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

151 ssues related to the clinical advancement of MAGL inhibitors are also discussed.

152 upport the potential clinical application of MAGL inhibitors as novel treatments for TNBC.

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

154 development and clinical characterization of MAGL inhibitors via noninvasive and quantitative PET ima

155 imization of a previously developed class of MAGL inhibitors led to the identification of compound 23

156 hiocarbamate derivatives as a novel class of MAGL inhibitors.

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

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

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

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

161 The development of MAGL inhibitors has been greatly limited by the side eff

162 YH134 can be used for estimating the dose of MAGL inhibitor at half-maximal peripheral target occupan

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

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

165 ermine whether the neuroprotective effect of MAGL inhibition is mediated by CB2R activation on specif

166 Considering the ubiquitous expression of MAGL throughout the whole body, the impact of various MA

167 e are cautiously optimistic, as the field of MAGL inhibitor development transitions from preclinical

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

169 Inhibition of MAGL has been proposed as an attractive approach for the

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

171 Preclinically, inhibition of MAGL is known to provide therapeutic benefits for a numb

172 Inhibition of MAGL offers unique advantages over the direct activation

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

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

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

176 abeling was found to exhibit a high level of MAGL specificity; this enabled cross-species measurement

177 y; this enabled cross-species measurement of MAGL brain expression (B(max)), assessment of in vivo bi

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

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

180 Overexpression of MAGL in nonaggressive cancer cells recapitulates this fa

181 ound to harness the therapeutic potential of MAGL inhibition.

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

183 The therapeutic potential of MAGL is linked to several diseases, including cancer.

184 The central role of MAGL in the metabolism of 2-AG makes it an attractive th

185 ted disorders; describe the current state of MAGL inhibitor drug development; and discuss biological

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

187 ntrol mice, MSDB-specific knockout of CB1 or MAGL bidirectionally modulated 2-AG signaling in the ven

188 we induced MSDB-specific knockout of CB1 or MAGL via injection of virally-delivered Cre recombinase

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

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

191 s significantly reduced by a brain-penetrant MAGL inhibitor but was unchanged by a peripherally restr

192 To explore the impact of peripheral MAGL occupancy on (R)-[(18)F]YH134 brain uptake, PET kin

193 Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing

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

195 1-carbodithioate] (CK37), as the most potent MAGL inhibitor within this series (IC(50) = 154 nM).

196 e side effects associated with the prolonged MAGL inactivation.

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

198 t was unchanged by a peripherally restricted MAGL inhibitor.

199 peripherally restricted, covalent reversible MAGL inhibitor that reduced neuropathic pain and inflamm

200 olidin-2-one derivatives as novel reversible MAGL inhibitors.

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

202 lore the therapeutic potential of reversible MAGL inhibitors.

203 which proved to be a very potent reversible MAGL inhibitor (IC(50) = 80 nM), selective for MAGL over

204 mparison with previously reported reversible MAGL PET radiotracers.

205 I-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a me

206 ly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversibl

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

208 which showed potent reversible and selective MAGL inhibition.

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

210 ng access to the highly potent and selective MAGL inhibitor 7o.

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

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

213 nd +/-73 (LEI-515) as a metabolically stable MAGL inhibitor with subnanomolar potency.

214 We review preclinical evidence supporting MAGL inhibition for the treatment of affective, trauma-r

215 Here, we targeted MAGL in TNBCs, using a potent carbamate-based inhibitor

216 ed miniaturized fluorescent probes targeting MAGL by incorporating a highly fluorescent boron-dipyrro

217 annabinoid-based pain therapeutics targeting MAGL and CB1Rs.SIGNIFICANCE STATEMENT Presynaptic G-prot

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

219 100-fold more potent in inhibiting FAAH than MAGL, would prevent spontaneous withdrawal in morphine-d

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

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

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

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

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

225 The MAGL target occupancy in the periphery was estimated usi

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

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

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

229 a heterogeneous distribution and matched the MAGL expression pattern in the mouse brain.

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

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

232 inhibitor structure that interacts with the MAGL active site.

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

234 Target occupancy studies with a therapeutic MAGL inhibitor revealed a dose-dependent reduction of (R

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

236 us distribution pattern with high binding to MAGL-rich brain regions in wild-type mouse brain slices,

237 ughout the whole body, the impact of various MAGL inhibitors on (R)-[(18)F]YH134 brain uptake and its

238 a highly promising PET probe for visualizing MAGL non-invasively in vivo and holds great potential to

239 In vitro MAGL enzyme activity assessment using 2-AG as the substr

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

241 ify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate

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

243 Associated with MAGL overexpression and the prognostic role in pancreati