Endocannabinoid Hydrolase Inhibitors: Potential Novel Anxiolytic Drugs

Figures & data

Figure 1 Composition of the endocannabinoid system. The endocannabinoid system consists of CB1R, CB2R, endocannabinoids, and their corresponding synthesizing and degrading enzymes. 2-AG and AEA, the primary endocannabinoids, are produced on demand and are synthesized from the postsynaptic terminals by DAGLα and NAPE-PLD, respectively, to activate presynaptic cannabinoid receptors. CB1R activation inhibits presynaptic neurotransmitter release and promotes astrocytic glutamate release. CB2R activation reduces microglial inflammatory factor production. 2-AG and AEA are enzymatically degraded to AA by MAGL and FAAH hydrolases, and can also be oxidatively degraded to PG-EA and PG-G by COX-2.

Abbreviations: CB1R, cannabinoid receptor 1; CB2R, cannabinoid receptor 2; 2-AG, 2-arachidonoylglycerol; AEA, anandamide; NAPE-PLD, N-acylphosphatidylethanolamine-specific phospholipase D; DAGLα, diacylglycerol lipase α; AA, arachidonic acid; MAGL, monoacylglycerol lipase; FAAH, fatty acid amide hydrolase; PG-EA, prostaglandin ethanolamide; PG-G, prostaglandin glycerol; COX-2, cyclooxygenase-2.

Table 1 Summary of the Anxiolytic Effects of MAGL Inhibitors in Preclinical Studies

Drug	Dose/Administration	Animal	Model	Test	Effects	References
JZL184	2, 10, 40 mg/kg, i.p	C57BL/6J mice, male	–	EPM; LDT	↑ percent time in open-arm; ↑ percent light time	[35]
	2 mg/kg, i.p	Sprague-Dawley rats, male and female	ELS	OFT	↑ activity level	[36]
	1, 3 mg/kg, i.p	C57BL/6J mice, male	ARS	EPM	↑ percent time in open-arm	[34]
	5, 8, 10, 40 mg/kg, i.p	ICR mice, male	ARS and Foot shock stress	LDT; NIH; EZM; OFT	↑ percent light time and distance; ↓ feeding latency and ↑ food consumption;↑ open arm entries and total distance, ↓ time immobile in open arm and exit latency; ↑ total distance and ↓ number of faeces	[37]
	3, 5, 10, 15 mg/kg, i.p	ICR mice, male	ARS	LDT	↑ percent light time, light distance, and total distance	[38]
	1 μg, intra-NAc microinjection	C57BL/6J mice, male	CSDS	OFT; LDT; EPM	↑ percent center time; ↑ time in light; ↑ percent time in open arm	[39]
	8 mg/kg, i.p	C57BL/6J mice, male	CUS	EPM; LDT	↑ duration and frequency in open arm; ↑ time and frequency in light compartment	[40]
	4, 8, 16 mg/kg, i.p	ICR mice, male	CRS	OFT; NIFS; EPM; MBT	No significance in OFT and EPM test; ↓ feeding latency; ↓ marble burying	[41]
	16 mg/kg, i.p	C57BL/6J mice, male	-	MBT	↓ marble burying	[42]
KML29	200 ng, intra-vmPFC microinjection	Fischer-344 rats, male	Tail shocks	Social exploration	↑ social exploration	[43]
	40 mg/kg, i.p		Tail shocks	Social exploration	↓ social exploration
MJN110	5, 10 mg/kg, i.p	Wistar rats, male and female	-	NIH	↑ feeding consumption	[44]
	10, 20 mg/kg, i.p	Wistar rats, male	ARS	EPM	↑ percent time in open-arm	[34]

Abbreviations: ARS, acute restraint stress; CRS, chronic restraint stress; CSDS, chronic social defeat stress; CUS, chronic unpredictable stress; ELS, early life stress; EPM, elevated plus maze; EZM, elevated zero maze; i.p, intraperitoneal; LDT, light-dark box test; MBT, marble burying test; NAc, nucleus accumbens; NIFS, novelty-induced feeding suppression; NIH, novelty-induced hypophagia; OFT, open-field test.

Figure 2 Schematic representation of the mechanism of anxiolytic action mediated by MAGL inhibitors. Briefly, the anxiolytic effects of MAGL are related to its maintenance of Glutamate/GABA balance, inhibition of neuroinflammation, and regulation of corticosterone levels.

Abbreviations: MAGL, monoacylglycerol lipase; CB1R, cannabinoid receptor 1; 2-AG, 2-arachidonoylglycerol; AMY, amygdala; PFC, prefrontal cortex; HPC, hippocampus; MSDB, medial septum and nucleus of the diagonal band; MHb, medial habenula; sEPSC, spontaneous excitatory postsynaptic currents; CB2R, cannabinoid receptor 2; COX-2, cyclooxygenase-2; AA, arachidonic acid; PGs, prostaglandins; LTs, leukotrienes; PG-G, prostaglandin glycerol; PGD2-G, prostaglandin D2-glyceryl ester; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; CORT, corticosterone.

Table 2 Summary of MAGL Inhibitors Derived from Natural Products

Compounds	Category	Source	Pharmacological Effects	Experiment Type	References
Betulinic acid, Cucurbitacin B, Euphol, Pristimerin	Triterpenes	–	Analgesic	In vitro and ex vivo	[99]
Dehydrocorydaline	Alkaloid	Corydalis yanhusuo	Analgesic	In vitro or in vivo	[106]
8-prenylnaringenin	Flavonoid	Humulus lupulus L.	Promotion of neurogenesis and neurodifferentiation	In vitro	[101]
Lepidine B&E	Alkaloid	Lepidium sativum L. seeds	Inhibition of β-amyloid production and accumulation	In vitro	[108]
Forsythiaside	Phenolic acid glycosides	Forsythia suspensa	Inhibition of β-amyloid production and accumulation	Ex vivo	[107]
α-amyrins, β-amyrins, Lupeol, Protium copal resin	Triterpenes	Protium copal	Analgesic, anti-inflammatory, anxiolytic	In vivo and in vitro	[100,109]
Jewenol A	Diterpenes	S.pseudorosmarinus aerial parts	Anticancer	In vitro	[105]
–	Phenylethanoid glycosides	C. phelypaea aerial parts	Anticancer	In vitro	[104]
–	–	Myristica fragrans methanol extracts	Anxiolytic, Antidepressant	In vitro	[102]

Table 3 Summary of the Anxiolytic Effects of FAAH Inhibitors in Preclinical Studies

Drug	Dose/Administration	Animal	Model	Test	Effects	References
URB597	0.1, 0.3, 1 mg/kg, i.p	C57BL/6J mice, male	SDS	NSF	↓ latency to feed	[122]
	0.3384 ng, 3.384 ng, 33.84 ng, intra-BNST microinjection	Wistar rats, male	ARS	EPM; CFC	No significance in EPM test; ↓ percentage of freezing behavior	[123]
	0.3 mg/kg, i.p	Sprague-Dawley rats, male	TMT exposure	EPM	↑ open arm time and entries, ↓ anxiety index	[124]
	3 mg/kg, i.p	Sprague-Dawley rats, female	Induced by poly I:C	OFT; EPM	↑ number of transition to inner arena; ↑ duration in open arm	[125]
	1 μg, intra-CeA microinjection	Wistar rats, male	CRS	EPM	↑ open arm time and entries	[115]
	1 mg/kg, i.p	C57BL/6J mice, male	CUS	EPM; LDT	↑ duration and frequency in open arm; ↑ time and frequency in light compartment	[40]
PF-3845	10 mg/kg, i.p	Wistar rats, male	Cafeteria diet exposure	OFT; EPM	↑ center zone entries and distance; ↑ open arm time and ↓ closed arm time	[126]
	1, 3, 10 mg/kg, i.p	C57BL/6J mice, male	–	EPM; LDT	↑ percent time in open-arm; ↑ percent light time	[35]
	0.1, 1, 10 mg/kg, i.p	ICR mice, female	ARS and Foot-shock stress	LDT; NIH; EZM; OFT	↑ percent light time and distance, no significance in NIH test, EZM test and OFT	[37]
	10 mg/kg, i.p	ICR mice, male	Foot-shock stress	LDT	↑ percent light time and light entries	[127]
URB937	1, 3 mg/kg, i.p	Wistar rats and Sprague-Dawley rats, male	SDS, TMT exposure	EPM; SAA	↑ open arm time and entries, ↓ closed arm time; ↓ time spent in non-social compartment and latency to access the social compartment, ↑ time spent in social compartment	[128]
PF-04457845	100 ng, 1 μg, icv	Sprague-Dawley rats, male	Colitis-induced anxiety	EPM	↑ open arm time	[129]
ST4070	3, 10, 30 mg/kg, p.o	CD1 mice, male	–	EPM	↑ open arm time	[130]
	10, 30 mg/kg, p.o	Wistar rats, male	–	LDT	↑ light time
JNJ5003	50 mg/kg, p.o	C57BL/6J mice, male	CRS	EPM	↑ time spent in the open arm, ↓ latency to enter the open arm	[114]

Abbreviations: ARS, acute restraint stress; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; CFC, contextual fear conditioning; CRS, chronic restraint stress, CUS-chronic unpredictable stress; EPM, elevated plus maze; EZM, Elevated zero maze; icv, intracerebroventricular; i.p, intraperitoneal; LDT, light-dark box test; NIH, novelty-induced hypophagia; NSF, novelty suppressed feeding; OFT, open-field test; SAA, social avoidance/approach; SDS, social defeat stress; TMT, 2,5-dihydro-2,4,5-trimethylthiazoline.

Figure 3 Schematic representation of the mechanism of anxiolytic action mediated by FAAH inhibitors. Briefly, the anxiolytic effects of FAAH are related to its maintenance of Glutamate/GABA balance, suppression of neuroinflammation, regulation of HPA axis, and promotion of neurogenesis and plasticity.

Abbreviations: FAAH, fatty acid amide hydrolase; CB1R, cannabinoid receptor 1; AEA, anandamide; AMY, amygdala; PFC, prefrontal cortex; AA, arachidonic acid; PGs, prostaglandins; IL-1β, Interleukin-1β; TNF-α, Tumor Necrosis Factor-α; iNOS, inducible nitric oxide synthase; TLRs, Toll-like receptors; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; CORT, corticosterone; corticotropin-releasing hormone receptor 1; NPY, neuropeptide Y; BDNF, brain-derived neurotrophic factor.

Table 4 Summary of FAAH Inhibitors Derived from Natural Products

Compounds	Category	Source	Pharmacological Effects	Experiment Type	References
Macamides	Alkaloid	Lepidium meyenii Walp	Relief of ischemic injury, analgesic, anti-inflammatory, neuroprotective	In vitro	[205, 206]
Silybin, isosilybin	Flavonolignans	Silybum marianum	Alleviate peripheral neuropathy	In vitro	[207]
–	–	Ashwagandha	Antioxidant	In vivo	[208]
–	Lanostane triterpenoids	Ganoderma lucidum	Suppress neuroinflammation	In vitro	[209, 210]
7-Hydroxyflavone, biochanin A, genistein	Isoflavone	Glycine max Merrill. germ, Trifolium pratense L.	Antidepressant, analgesic	In vivo and in vitro	[204, 211]
Isorhamnetin, kaempferol, quercetin	Flavonoid	Moricandia sinaica aerial parts	Analgesic, antipyretic, anti-inflammatory	In vivo and in vitro	[212, 213]
Kaempferol	Flavonoid	–	Anxiolytic	In vivo and in vitro	[203]
Eugenol, β-caryophyllene	Terpenoid	Harpagophytum procumbens root	Anti-arthritic	In vitro	[214]
Citral	Monoterpene	Cymbopogon citratus	Anti-inflammatory, analgesic	In vivo and in vitro	[215]
Licarin A, 5′-methoxylicarin A, malabaricone C	Phenol	Myristica fragrans Houtt.	Anxiolytic	In vivo and in vitro	[216]
Linalool, Linalyl acetate	Essential oil	Lavandula angustifolia Mill.	Relief of neuropathic pain, anxiolytic, antidepressant	In vivo and in vitro	[217]
Cannabidiol, tetrahydrocannabinol, cannabigerol	Phenol	Cannabis sativa L.	Antioxidant, inhibition of inflammatory bowel disease-associated hypermobility, anxiolytic	In vivo and in vitro	[218, 219]

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