Development of the first potent and specific inhibitors of endocannabinoid biosynthesis

Bisogno, Tiziana; Cascio, Maria Grazia; Saha, Bijali; Mahadevan, Anu; Urbani, Paolo; Minassi, Alberto; Appendino, Giovanni; Saturnino, Carmela; Martin, Billy R.; Razdan, Raj K.; Marzo, Vincenzo Di

doi:10.1016/j.bbalip.2005.12.009

Cited by 118 publications

(110 citation statements)

References 27 publications

(55 reference statements)

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“…4 b and c and previous evidence (18) suggest that the three eCB pathways are not identical. Because THL antagonizes lipase activities downstream of Ca 2ϩ (24), these experiments are compatible with the concept that a rise in [Ca 2ϩ ] i primes cells independently of DGL. Moreover, the priming mechanism appears to be distinct from the Ca 2ϩ -dependent and eCB mAChR pathways.…”

Section: Priming Of Mglur-mediated Ecb Mobilizationsupporting

confidence: 72%

“…S2). RHC 80267 is a comparatively weak DGL inhibitor in biochemical assays whereas tetrahydrolipstatin, tetrahydrolipstatin (THL; orlistat), is more potent (24), and it inhibits some eCB responses (18,(25)(26)(27). We found that extracellular application of 10 M THL reduced DSI and virtually abolished the carbachol (CCh)-induced eCB mAChR response without preventing eCB mGluR priming (Fig.…”

Section: Priming Of Mglur-mediated Ecb Mobilizationmentioning

confidence: 86%

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Metaplastic control of the endocannabinoid system at inhibitory synapses in hippocampus

Edwards

Zhang

Alger

2008

Proc. Natl. Acad. Sci. U.S.A.

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The modifiability of neuronal response plasticity is called ''metaplasticity.'' In suppressing synaptic inhibition and facilitating induction of long-term excitatory synaptic plasticity, endocannabinoids (eCBs) act as agents of metaplasticity. We now report the discovery of a calcium-dependent mechanism that regulates eCB mobilization by metabotropic glutamate receptor (mGluR) activation. The switch-like mechanism primes cells to release eCBs and requires a transient rise in intracellular Ca 2؉ concentration ([Ca 2؉ ]i) but not concurrent activation of mGluRs. Conversely, short-term, [Ca 2؉ ]i-dependent eCB release can be persistently enhanced by mGluR activation. Hence, eCBs are also objects of metaplasticity, subject to higher levels of physiological control.2-arachidonyl glycerol ͉ calcium ͉ GABA ͉ metabotropic glutamate ͉ muscarinic E ndocannabinoids (eCBs) are important signaling molecules that modulate synaptic strength throughout the CNS (for reviews, see refs. 1-4). They control both short-and long-term forms of synaptic plasticity and are implicated in many animal behaviors. eCBs, which are fatty acid derivatives, are synthesized directly by enzymatic action on cellular plasma membrane phospholipids. Because they are not stored before use, eCBs are said to be available ''on-demand.'' Although the first identified eCB was anandamide, 2-arachidonyl glycerol (2-AG) is probably the principal ligand for cannabinoid receptors (CB1Rs) in much of the brain (5, 6). 2-AG synthesis is thought to proceed via phospholipase C (PLC) and the action of diacylglycerol lipase (DGL) on the PLC product, diacyglycerol (DAG). eCBs are retrograde messengers, and their release from postsynaptic cells may also be regulated. Physiological techniques cannot distinguish among synthesis, release, and transport processes, and we use the term ''mobilization'' to encompass all steps between stimulation of the eCB system and activation of CB1R. eCB mobilization occurs after either a rise in the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) (7-9) or activation of G protein-coupled receptors (GPCRs), including dopaminergic (10, 11), metabotropic glutamatergic (12, 13), and muscarinic cholinergic (14) receptors.In the hippocampus, CB1R is present in high concentrations on the synaptic terminals of certain GABAergic interneurons (15). Ca 2ϩ -dependent eCB mobilization transiently suppresses CA1 pyramidal cell evoked inhibitory postsynaptic currents (eIPSCs) (7, 8), a retrograde signal process called DSI (1). Group I metabotropic glutamate receptor (mGluR) activation potently stimulates eCB mobilization, thereby depressing eIPSCs (12, 13) or excitatory postsynaptic currents (EPSCs) for short (seconds to minutes) or long (minutes to hours) (16, 17) periods of time, depending on the stimulation conditions.Various stimuli use different biochemical pathways for eCB mobilization, which can be designated eCB mGluR , eCB mAChR , and eCB Ca . Pharmacological inhibitors of PLC abolish hippocampal long-term IPSC suppression (eCB-iLTD) initiated by...

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Section: Priming Of Mglur-mediated Ecb Mobilizationsupporting

confidence: 72%

Section: Priming Of Mglur-mediated Ecb Mobilizationmentioning

confidence: 86%

Metaplastic control of the endocannabinoid system at inhibitory synapses in hippocampus

Edwards

Zhang

Alger

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Cultured neurons were maintained in DMEM/F12, supplemented with 1% B27/1% glutamine/1% penicillin/streptomycin for 3-6 days (7). Ligands were first added 12 h after cell seeding and replenished every other day (7), except for O-3841 (1 M) (19), which was used between days 2-6 in vitro. Density of glutamatergic neurons was defined as a ratio of VGLUT1 ϩ /TuJ1 ϩ cells from Ն10 randomly selected view fields per coverslip.…”

Section: Methodsmentioning

confidence: 99%

Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning

Mulder

Aguado²,

Keimpema³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

270

356

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Endocannabinoids (eCBs) have recently been identified as axon guidance cues shaping the connectivity of local GABAergic interneurons in the developing cerebrum. However, eCB functions during pyramidal cell specification and establishment of longrange axonal connections are unknown. Here, we show that eCB signaling is operational in subcortical proliferative zones from embryonic day 12 in the mouse telencephalon and controls the proliferation of pyramidal cell progenitors and radial migration of immature pyramidal cells. When layer patterning is accomplished, developing pyramidal cells rely on eCB signaling to initiate the elongation and fasciculation of their long-range axons. Accordingly, CB 1 cannabinoid receptor (CB1R) null and pyramidal cellspecific conditional mutant (CB 1R f/f,NEX-Cre ) mice develop deficits in neuronal progenitor proliferation and axon fasciculation. Likewise, axonal pathfinding becomes impaired after in utero pharmacological blockade of CB 1Rs. Overall, eCBs are fundamental developmental cues controlling pyramidal cell development during corticogenesis.excitation ͉ glutamate ͉ layer patterning ͉ neocortex ͉ neurogenesis P yramidal cell specification follows a sequential scenario in the developing cerebrum: commitment of progenitor cells to the neuronal lineage occurs in the subcortical proliferative ventricular zone (VZ) and subventricular zone (SVZ). Immature pyramidal cells undergo radial migration to populate the cortical plate (CP) (1), where they acquire layer-specific neurochemical and morphological diversity (2). Pyramidal cell positioning and patterning of their corticofugal and intracortical axons is in part achieved via transcriptional control acting throughout cellular identification (2). However, epigenetic microenvironmental cues, provided by neural progenitors, radial glia, and immature neurons, are also fundamental in attaining cortical cell identity with particularly robust effects on pathfinding and directional growth of long-range axons (3).Endocannabinoids [eCBs; anandamide (AEA) and 2-arachidonoylglycerol] control various forms of synaptic plasticity at cortical glutamatergic synapses in the postnatal brain (4) through functional CB 1 cannabinoid receptors (CB 1 Rs) (5). During brain development, eCBs control neuronal fate decision (6), interneuron migration (7), and axonal specification (8). Developmental eCB actions are underpinned by a temporally defined assembly of functional eCB signaling networks with coincident expression of sn-1-diacylglycerol lipases (DAGL␣/␤) (9) and N-arachidonoyl-phosphatidyl ethanolamine (NAPE)-selective phospholipase D involved in eCB synthesis, fatty-acid amide hydrolase (FAAH) (an enzyme preferentially degrading AEA), and CB 1 Rs (8). The selective axonal targeting of CB 1 Rs and DAGLs in immature neurons suggests that eCBs may function in either cell-autonomous (6, 9) or target-derived (8) manner to control axonal elongation and postsynaptic target selection, respectively.Although recent findings in both mammals (8) and nonmammalian v...

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“…6,7 In recent years a few novel MGL inhibitors were discovered. 4,[8][9][10][11] Until recently, the only selective small-molecule inhibitor of MGL was URB602 (FIG. 1), a carbamate derivative possessing a moderate activity (half-maximal inhibitory concentration, IC 50 = 75±7 µM in rat brain MGL expressed in HeLa cells and 28±4 µM in native rat brain MGL).…”

Section: Introductionmentioning

confidence: 99%

Identification of a Bioactive Impurity in a Commercial Sample of 6‐Methyl‐2‐p‐Tolylaminobenzo[d][1,3]Oxazin‐4‐One (URB754)

et al. 2007

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The compound URB754 was recently identified as a potent inhibitor of the endocannabinoid‐deactivating enzyme monoacylglycerol lipase (MGL) by screening of a commercial chemical library. Based on HPLC/MS, NMR and EI/MS analyses, the present paper shows that the MGL‐inhibitory activity attributed to URB754 is in fact due to a chemical impurity present in the commercial sample, identified as bis(methylthio)mercurane. Although this organomercurial compound is highly potent at inhibiting MGL (IC50 = 11.9±1.1 nM), its biological use is prohibited by its toxicity and target promiscuity.

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Development of the first potent and specific inhibitors of endocannabinoid biosynthesis

Cited by 118 publications

References 27 publications

Metaplastic control of the endocannabinoid system at inhibitory synapses in hippocampus

Metaplastic control of the endocannabinoid system at inhibitory synapses in hippocampus

Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning

Identification of a Bioactive Impurity in a Commercial Sample of 6‐Methyl‐2‐p‐Tolylaminobenzo[d][1,3]Oxazin‐4‐One (URB754)

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