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New Product Spotlight: Endocannabinoid Modulators

February 6, 2018

The endocannabinoid system is a set of proteins and endogenous ligands that regulates a variety of biological processes. It consists of cannabinoid receptors 1 (CB1) and 2 (CB2), the natural ligands 2-arachidonyl glycerol (2-AG) and N-arachidonylethanolamide (AEA or Anandamide), as well as proteins responsible for the hydrolysis of these ligands, such as monoacyl glycerol lipase (MAGL), fatty acid amide hydrolase (FAAH) and alpha/beta hydrolase domain 6 (ABHD6). CB1 is located mainly in brain tissues, while CB2 is found in the periphery. Endocannabinoid modulation is a research topic in neuroscience, immunology, cancer and obesity research.

Cannabinoid receptors 1 and 2 are G-protein coupled receptors (GPCRs). The results of activation/inhibition of CB1 and CB2 are still being explored.

CB Mixed Agonists

Besides endogenous ligands 2-AG and AEA, many synthetic endocannabinoids have been discovered. Mixed agonists (which interact with both CB1 and CB2) include WIN 55,212-2 and CP 55,940. Both of these agonist are able stimulate cannabinoid signaling, with no preference between the two receptors. Stimulation of CB1 and CB2 has been tied to analgesia, anti-diabetic, anti-obesity and anti-inflammation.

W317520 WIN 55212-2

C600000 CP 55,940

 

Selective CB antagonists

Antagonism of the cannabinoid receptors is under study for decreasing CB signaling. CB antagonists have been used in neuroscience, cancer and immunology research. AM251, a selective CB1 inverse agonist demonstrated benefits in an anti-obesity system. AM630, a selective CB2 inverse agonist, activates TRPA1 in sensory neurons.

CB1 Antagonists/Inverse Agonists

A480000 AM251

R3449 Rimonabant

CB2 Antagonists/Inverse Agonists

A480010 AM630

S680000 SR144528

J766160 JTE907

 

CB2 Agonists

CB2 selective agonists are ubiquitous throughout current academic literature. Synthetic CB2 agonists have been used to study the role of endocannabinoids in neurodegenerative disorders, diabetes, obesity and cancer. Agonists of the CB2 receptor have especially shown benefits as analgesic and anti-allodynic compounds.

L000033 L-759,633

H800010 HU308

J889290 JWH 133

J889280 JWH 015

G880000 GW 405833

A480020 AM1241

S182680 SER601

M184770 4-O-methylhonokiol

 

FAAH Inhibitors

Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of AEA to arachidonic acid. Inhibition of FAAH results in an increase in AEA, which can stimulate CB1 and CB2 and activate down stream signaling pathways. FAAH inhibition is under investigation for pain attenuation and the reduction of neuro-inflammation. FAAH inhibitor URB597 demonstrates analgesic effects in mice. Inhibitor PF-3845 also reduces pain in mice stimulated with LPS, and reduces inflammation in mice models for traumatic brain injury.

U682040 URB597

P200000 PF-3845

 

MAGL Inhibitors

Monoacylglycerol lipase (MAGL) is responsible for the hydrolysis of 2-AG to arachidonic acid. Increasing the amount of 2-AG stimulates cannabinoid signaling. Inhibition of MAGL increases 2-AG, showing the benefits of increased 2-AG. JZL 184, an inhibitor of MAGL decreases pain in multiple mouse models, showing anti-nociceptive and reducing pain-related to cancer drugs in mice. URB602, another inhibitor of MAGL, also demonstrates anti-nociceptive properties.

J974440 JZL 184

U682042 URB602

 

ABHD6 Inhibitors

Alpha/Beta hydrolase domain 6 (ABHD6) also hydrolyzes 2-AG to arachidonic acid. The ABHD inhibitor WWL70 reduces weight gain in diet-induced obese mice. It also has anti-inflammatory properties by reducing the amount of pro-inflammatory prostaglandin expression.

W894440 WWL70

 

References:

Aquirre-Rueda D, Guerra-Ojeda S, Aldasoro M et al. WIN 55,212-2, agonist of cannabinoid receptors, prevents amyloid beta1-42 effects on astrocytes in primary culture. PLoS One. 2015 Apr 13;10(4):e0122843. PMID: 25874692

Hamamoto DT, Giridharagopalan S, and Simone DA. Acute and chronic administration of the cannabinoid receptor agonist CP 55,940 attenuates tumor-evoked hyperalgesia. Eur J Pharamacol. 2007 Mar 8;558(1-3): 73-87. PMID: 17250825.

Patil M, Patwardhan A, Salas MM, et al. Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons. Neuropharmacology, 2011. Sep;61(4):778-88. PMID: 21645531.

Jenkin KA, O’Keefe L, Simcocks AC, et al. Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats. J Endocrin. 2015 May;225(2)113-24. PMID: 25804605.

Negrete R, Hervera A, Leazez S et al. The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids. PLoS One. 2011;6(10):e26688. PMID: 22031841.

Ibrahim MM, Deng H, Zvonok A et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci USA. 2003 Sep 2;100(18):10529-33. PMID: 12917492.

Kwilasz AJ, Abdullah RA, Poklis JL et al. Effects of the fatty acid amide hydrolase inhibitor URB597 on pain-stimulated and pain-depressed behavior in rats. Behav Pharmacol. 2014 Apr;25(2):119-29. PMID: 24583930

Booker L, Kinsey SG, Abdullah RA et al. The fatty acid hydrolase (FAAH) inhibitor PF-3845 acts in the nervous system to reverse LPS-induced tactile allodynia in mice. Br J Pharmacol. 2012 Apr;165(8):2485-96. PMID: 21506952.

Comelli F, Giagnoni G, Bettoni I et al. The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation. Br J Pharmacol. 2007 Nov;152(5):787-94. PMID:17700715.

Woodhams SG, Wong A, Barrett DA et al. Spinal administration of the monoacylglycerol lipase inhibitor JZL 184 produces robust inhibitory effects on nociceptive processing and the development of central sensitization in the rat. Br J Pharmacol. 2012 Dec;167(8):1609-19. PMID: 22924700.

Tanaka M, Moran S, Wen J et al. WWL70 attenuates PGE2 production derived from 2-arachidonoylglycerol in microglia by ABHD6-independent mechanism. J Neuroinflammation. 2017 Jan 10;14(1):7. PMID: 28086912.

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