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ABSTRACT
Introduction
Cannabinoid receptor type 2 (CB2R), predominantly expressed in immune tissues, is believed to play a crucial role within the body’s protective mechanisms. Its modulation holds immense therapeutic promise for addressing a wide spectrum of dysbiotic conditions, including cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, and autoimmune diseases, as well as lung disorders, cancer, and pain management.
Areas covered
This review is an account of patents from 2016 up to 2023 which describes novel CB2R ligands, therapeutic applications, synthesis, as well as formulations of CB2R modulators.
Expert opinion
The patents cover a vast, structurally diverse chemical space. The focus of CB2R ligand development has shifted from unselective dual-cannabinoid receptor type 1 (CB1R) and 2 agonists toward agonists with high selectivity over CB1R, particularly for indications associated with inflammation and tissue injury. Currently, there are at least eight CB2R agonists and one antagonist in active clinical development. A better understanding of the endocannabinoid system (ECS) and in particular of CB2R pharmacology is required to unlock the receptor’s full therapeutic potential.
Article highlights
CB2R is a fundamental part of a biological protective system that has significant therapeutic potential for limiting tissue injury in a variety of pathological conditions.
CB2R ligands can be divided into endogenous cannabinoids (endocannabinoids, eCBs) and their analogues, marijuana plant-derived, and synthetic cannabinoids encompassing a range of mechanisms of action, such as agonism, inverse agonism, and allosteric modulation.
This comprehensive review scrutinizes 748 CB2R patents filed from January 2016 to the end of October 2023, with a particular focus on drug substance patents.
Among over 20 clinically investigated CB2R ligands, primarily agonists, three have successfully launched, while more than nine are currently in active clinical development.
The newly discovered ligands showcase a wide spectrum of structural diversity, with several demonstrating activity in preclinical animal models of both peripheral and central inflammatory diseases.
The majority of the non-drug substance patent applications focuses on biologically active cannabinoids derived from the marijuana plant, including Δ9-THC and cannabidiol.
Abbreviations
| 2-AG | = | 2-Arachidonoylglycerol |
| AA | = | Arachidonic acid |
| AChE | = | Acetylcholinesterase |
| AD | = | Alzheimer’s disease |
| ADME(T) | = | Absorption, distribution, metabolism, excretion (and toxicity) |
| AEA | = | Anandamide |
| AIDS | = | Acquired immunodeficiency syndrome |
| ALS | = | Amyotrophic lateral sclerosis |
| APP | = | Amyloid precursor protein |
| BACE-1 | = | β-Site amyloid precursor protein cleaving enzyme 1 |
| BBB | = | Blood-brain barrier |
| BuChE | = | Butyryl choline esterase |
| cAMP | = | Cyclic adenosine monophosphate |
| CB1R | = | Cannabinoid type 1 receptor, cannabinoid receptor 1 |
| CB2R | = | Cannabinoid type 2 receptor, cannabinoid receptor 2 |
| CBC | = | Cannabichromene |
| CBD | = | Cannabidiol |
| CBDA | = | Cannabidiolic acid |
| CBG | = | Cannabigerol |
| CBGA | = | Cannabigerolic acid |
| CBN | = | Cannabinol |
| CNS | = | Central nervous system |
| Colla | = | Collagen |
| COVID-19 | = | Coronavirus disease 2019 |
| COX | = | Cyclooxygenase |
| CYP | = | Cytochrome P450 enzyme |
| DAGL | = | Diacylglycerol lipase |
| DMH | = | Dimethylheptyl |
| EAE | = | Experimental autoimmune encephalomyelitis |
| eCBs | = | Endocannabinoids |
| EC(S) | = | Endocannabinoid (system) |
| ERK | = | Extracellular signal-regulated kinase |
| F | = | Bioavailability |
| FAAH | = | Fatty acid amide hydrolase |
| GPCR | = | G protein- coupled receptor |
| GTP | = | Guanosine-5’-triphosphate |
| HTRF | = | Homogeneous time-resolved Förster resonance energy transfer |
| Hp | = | Hemopressin |
| IBS | = | Irritable bowel syndrome |
| IOP | = | Intraocular pressure |
| i.p. | = | Intraperitoneal |
| i.v. | = | Intravenous |
| KO | = | Knockout |
| LPS | = | Lipopolysaccharide |
| MAGL | = | Monoacylglycerol lipase |
| mRNA | = | Messenger ribonucleic acid |
| MS | = | Multiple sclerosis |
| MTT | = | 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide |
| NAPE-PLD | = | N-acyl phosphatidyl-ethanolamine-specific phospholipase D |
| (N)ASH | = | (Non)-alcoholic steatohepatitis |
| NF-κB | = | Nuclear factor kappa-light-chain-enhancer of activated B cells |
| NMDA | = | N-methyl-D-aspartate |
| PAM | = | Positive allosteric modulator |
| PBMC | = | Peripheral blood mononuclear cells |
| PET | = | Positron emission tomography |
| PD | = | Pharmacodynamic |
| PD-P/L1 | = | Programmed cell death protein/ligand 1 |
| PK | = | Pharmacokinetic |
| p.o. | = | Per oral |
| PPAR | = | Peroxisome proliferator-activated receptor |
| PSA | = | Polar surface area |
| QSAR | = | Quantitative structure–activity relationship |
| RANKL | = | Receptor activator of NF-κB ligand |
| SAR | = | Structure–activity relationship |
| s.c. | = | Subcutaneous |
| siRNA | = | Small interfering ribonucleic acid |
| SMA | = | Smooth muscle actin |
| t1/2 | = | Half life |
| TgAPP | = | Transgenic mouse model of amyloid precursor protein |
| TGF | = | Transforming growth factor |
| THC | = | Tetrahydrocannabinol |
| THCA | = | Tetrahydrocannabinolic acid |
| TNF | = | Tumor necrosis factor |
| TRPV1 | = | Transient receptor potential cation channel subfamily V member 1 |
| XTT | = | 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2 H-tetrazolium-5-carboxanilide |
Declaration of interest
U. Grether is a full-time employee of F. Hoffmann-La Roche LTD.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Supplementary materials
Supplemental data for this article can be accessed online at https://doi.org/10.1080/13543776.2024.2368745