The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases
Abstract
:1. Introduction
1.1. History
1.2. Components of the ECS
2. The ECS as a Therapeutic Target
2.1. Mood and Anxiety Disorders
2.2. Pain Management
2.3. Cannabinoids as an Alternative to Opioids
2.4. Inflammation
2.5. Cardiovascular Disorders
2.5.1. Diabetes
2.5.2. Stroke
2.6. Cancer
3. Neurological/Neurodegenerative Diseases
3.1. Schizophrenia
3.2. Epilepsy
4. Autoimmune Diseases
4.1. Blood–Brain Barrier (BBB) (Also Referred to as the “Blood–Spinal Cord Barrier” (BSCB))
4.2. Multiple Sclerosis
4.3. Rheumatoid Arthritis
4.4. Disturbances of the Bowel and Inflammatory Bowel Disease (IDB)
5. Medical Cannabis in Dermatology
5.1. Acne
5.2. Psoriasis
5.3. Eczema
5.4. Fibrotic Skin Diseases
6. Eating Disorders
Anorexia Nervosa
7. HIV/AIDS-Related Disorders
8. Cannabinoids for the Treatment of Hepatitis B Virus
9. Cannabinoids Used to Modulate the ECS in Cannabinoid-Research
Central CB1R Agonists | Biological Effect(s) and/or Mechanism of Action | Reference | |
---|---|---|---|
i. | Δ9-THC (partial agonist) |
| [88,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321] |
ii. | WIN55,212-2 (also a CB2R agonist) |
| [322,323,324] [325,326,327,328] |
iii. | ACPA (Arachidonylcyclopropylamide) |
| [329,330,331] |
CB1R Allosteric Modulators | Biological Effect(s) and/or Mechanism of Action | Reference | |
---|---|---|---|
i. | GAT211 (positive allosteric modulators (PAM)(racemic)) |
| [332,333,334,335,336] |
ii. | GAT228 (R-enantiomer) |
| [336,337,338] |
iii. | GAT229 (S-enantiomer) |
| [336,337] |
iv. | ORG27569 (negative allosteric modulator (NAM)) |
| [339,340,341,342,343,344] |
Peripheral CB1R Agonists (Aka Peripherally Restricted Cannabinoid 1 Receptor (PRCB)) | Biological Effect(s) and/or Mechanism of Action | Reference | |
---|---|---|---|
i. | 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (“PrNMI” aka 2-“5u” |
| [87,345,346] |
ii. | 4-{2-[(1E)-1-[(4-Methoxynaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (2-5j) |
| [346] |
iii. | 2-5j (2-5j) |
| [346] |
CB2R Agonists | Biological Effect(s) and/or Mechanism of Action | Reference | |
---|---|---|---|
i. | AM1241 (University of Connecticut) |
| [136,347,348,349,350,351] |
ii. | A-76260 |
| [352] |
iii. | HU-308 (Hebrew University) |
| [353,354,355] |
iv. | GSK554418A | Acute/chronic pain | [356] |
v. | GW842166X | Inflammatory pain | [357] |
vi. | GW405833 |
| [358] |
vii. | GP1a |
| [359,360,361] |
viii. | JWH015 |
| [198,360,361,362,363,364,365] |
ix. | JWH133 |
| [360] [366,367,368,369,370] |
CB1R Antagonists | Biological Effect(s) and/or Mechanism of Action | Reference | |
---|---|---|---|
i. | SR141716A (Rimonabant)—the first developed CB1R antagonist. Now discontinued due to unwanted side effects such as depression, anxiety, and suicidal thoughts. |
| [6,136,372,373] |
ii. | AM251 |
| [374,375,376] |
iii. | SLV-326 (Solvay) |
| [136] |
iv. | LY320135 (Lilly) |
| [136,372,377] |
Neutral Antagonists | |||
v. | AM4113 |
| [136,378,379,380,381,382] |
vi. | O-2654 (Organix) |
| [136] |
vii. | AM5171 (University of Connecticut) |
| [6,136,272,338,373] |
Endocannabinoid-Like Compounds (Fatty-Acid Ethanolamides) | Biological Effect(s) and/or Mechanism of Action | Reference | |
---|---|---|---|
i. | OEA (an endogenous PPAR-α agonist) |
Via binding to peroxisome proliferators-activate receptor-α (PPAR- α) | [136] |
ii. | Palmitoylethanolamide (PEA) |
| [136] |
iii. | N-oleoyl-ethanolamide | May act as an alternative substrate for FAAH, and in doing so, inhibit the degradation of AEA | [383,384] |
iv. | N-linoleoyl-ethanolamide | May act as an alternative substrate for FAAH, and in doing so, inhibit the degradation of AEA | [383,384] |
v. | N-arachidonoyl-glycine | May act as an alternative substrate for FAAH, and in doing so, inhibit the degradation of AEA | [384,385,386] |
vi. | N-acyl-taurine | May act as an alternative substrate for FAAH, and in doing so, inhibit the degradation of AEA | [383,384,387] |
vii. | N-palmitoyl-ethanolamide | Reduced expression of FAAH | [384,388] |
Synthetic Cannabinergic Agonists | Biological Effect(s) and/or Mechanism Of Action | Reference | |
---|---|---|---|
i. | WIN55212-2 (Winthrop)
|
| [6,58,136,389,390] |
ii. | CP-55940 (Pfizer) |
| [136] |
iii. | URB-597 (aka KDS-4103) (targets FAAH) |
| [391] [6] |
iv. | PF-04457845 (Pfizer—targets FAAH) | Pain disorders (including osteoarthritis) | [342] |
v. | V158866 (Pfizer—targets FAAG) | Pain disorders (including osteoarthritis) | [6] |
Drugs That Inhibit the Cellular Uptake of Cannabinoids | Mechanism of Action | Reference | |
---|---|---|---|
i. | CBD | Inhibition of FAAH | [394] |
ii. | LY-2183240 | Inhibition of FAAH | [395] |
iii. | V-158866 (Vernalis) | Inhibition of FAAH | [396] |
iv. | VER-156084 (Vernalis) | Inhibition of FAAH | [397,398] |
v. | URB597 (KDS-4103, Kadmus Pharmaceuticals), | Inhibition of FAAH | [399,400] |
vi. | PF750 and PF-655 | Inhibition of FAAH | [393] |
Drugs That Inhibit the Deactivation | Biological Effect(s) and/or Mechanism of Action | Reference | |
---|---|---|---|
i. | AM404 | Blocks endocannabinoid transport | [136] |
ii. | OMDM-8 | Blocks endocannabinoid transport | [136] |
iii. | AM1172 (University of Connecticut/University of California) | Blocks endocannabinoid transport | [136] |
iv. | FAAH (fatty acid amide hydrolase) | Deactivates/degrades AEA | [136] |
v. | MAGL (monoacylglycerol) | Deactivates/degrades 2-AG | [136] |
10. Conclusions and Future Direction
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
2-AG | 2-arachidonoylglycerol |
AEA | N-arachidonoyl ethanolamide |
CB1R | Cannabinoid receptor type 1 |
CB2R | Cannabinoid receptor type 2 |
FDA | Food & Drug Administration |
NSAIDs | Nonsteroidal anti-inflammatory drugs |
Δ9-THC | Δ9-Tetrahydrocannabinol |
Δ9-THCA | Δ9-tetrahydrocannabinolic acid |
Δ9-THCV | Δ9-tetrahydrocannabivarin |
AM251 | N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide |
AM281 | N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide |
AM630 | 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone |
AM1241 | (2-iodo-5-nitrophenyl)-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl]-methanone |
AT | Anandamide transporter |
ACPA | Arachidonylcyclopropylamide |
Aβ | Beta-amyloid |
CB | Cannabinoid |
CBD | Cannabidiol |
CBDL | Cannabinodiol |
CBC | Cannabichromene |
CBCV | Cannabichromevarin |
CBL | Cannabicyclol |
CBE | Cannabielson |
CBG | Cannabigerol |
CBGV | Cannabigerovarin |
CBGM | Cannabigerol Monoethyl Ether |
CBN | Cannabinol |
CBT | Cannabitriol |
CBV | Cannabivarin |
COX2 | cyclooxygenase subtype 2 |
CP55940 | (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol |
ERK | Extracellular-regulated kinase |
FAAH | Fatty acid amide hydrolase |
GI | Gastrointestinal |
GCPR | G-Coupled Protein Receptor |
HU-210 | (6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol |
JWH-015 | (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone |
JWH-133 | 3-(1,1-dimethylbutyl)-6,6,9-trimethyl-6α,7,10,10α-tetrahydro-6H-benzo[c]chromene |
PPARγ | Peroxisome proliferator-activated receptor γ |
TRVP1 | Transient receptor potential vanilloid type 1 |
MAP | Mitogen-activated protein kinase |
R-(+)-WIN55212 | (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone |
SR141716A | N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride |
SR144528 | N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide |
DAGL | Diacylglycerol lipase |
MAGL | Monoacylglycerol lipase |
NAPE-PLD | N-acetyl-phosphatidyl-ethanolamine-hydrolyzing phospholipase D |
PEA | Palmitoylethanolamide |
OEA | Oleoylethanolamine |
FAAH | Fatty acid amide hydrolase |
NAAH | N-acylethanolamine acid amide hydrolase |
ABHD6 | Alpha/beta-Hydrolase domain containing 6 |
ABHD12 | Alpha/beta-Hydrolase domain containing 12 |
GABA | Gamma aminobutyric acid |
GPR55 | G-protein coupled receptor 55 |
GPR18 | G-protein coupled receptor 18 |
GPR119 | G-protein coupled receptor 119 |
FABS | Fatty Acid Binding Protein |
HSP70s | 70 kilodalton heat shock proteins |
AMT | Anandamide membrane transporter |
EMT | Endocannabinoid membrane transporter |
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Endo-Cannabinoids (“Endogenous Cannabinoids”/ eCBs) | Enzymes | Receptors | Transport Proteins | |
---|---|---|---|---|
Synthesizing | Degradative | |||
Synthetic Cannabinoids | Therapeutic Window | References | |
---|---|---|---|
1. | HU-308 and AM-124 (CB2R agonists) | Pain and inflammation | [6] |
2. | Pyrimidinecarboxamide (and its derivatives) (CB2R modulators) | Acute, chronic, and inflammatory pain | [6] |
3. | JWH-133 (intrathecal administration) | Reduction in post-operative hypersensitivity | [57] |
4. | Peripherally restricted CB1R agonists | Chronic pain | [58] |
Disorder/Property | Reference | |
---|---|---|
1. | Inflammatory bowel diseases such as Chron’s disease, ulcerative colitis and irritable bowel syndrome | [212,213,214,215,216,217,218,219,220,221,222] |
2. | Secretion and motility-related disorders | [223] |
3. | Ant-secretory | [224] |
4. | Digestive | [225] |
5. | Appetite-stimulant | [225] |
6. | Anti-flatulent | [225] |
7. | Anti-spasmodic (for diarrhoea and colic) | [225] |
8. | Antiparasitic (for internal and external worms) | [225] |
9. | Gastric ulcers | [225] |
10. | Gastric neuroses | [225] |
11. | Gastralgia (indigestion) | [225] |
12. | Dispepsia | [225] |
13. | Diarrhoea | [212,226] |
14. | Abdominal cramping | [226] |
15. | Abdominal pain | [226] |
16. | Loss of appetite | [227] |
17. | Anorexia | [219] |
18. | Anti-inflammatory | [212] |
19. | Anti-emetic | [212] |
20. | Analgesic | [212] |
CB1R-Selective Ligands | CB1 R/CB2R Ligands | CB2R-Selective Ligands | ||
---|---|---|---|---|
Agonist | Antagonist/ Inverse Agonists | Agonists | Antagonist/ Inverse Agonists | Agonist |
|
|
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Lowe, H.; Toyang, N.; Steele, B.; Bryant, J.; Ngwa, W. The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases. Int. J. Mol. Sci. 2021, 22, 9472. https://doi.org/10.3390/ijms22179472
Lowe H, Toyang N, Steele B, Bryant J, Ngwa W. The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases. International Journal of Molecular Sciences. 2021; 22(17):9472. https://doi.org/10.3390/ijms22179472
Chicago/Turabian StyleLowe, Henry, Ngeh Toyang, Blair Steele, Joseph Bryant, and Wilfred Ngwa. 2021. "The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases" International Journal of Molecular Sciences 22, no. 17: 9472. https://doi.org/10.3390/ijms22179472