Allosteric Modulation of Cannabinoid Receptor 1—Current Challenges and Future Opportunities
Abstract
:1. Introduction
2. Allosteric Modulation of GPCRs
3. CB1R and Its Ligands
4. CB1R Activation and Signaling
5. CB1R Biased Signaling
6. Other Novel Modes of CB1R Activation
7. A Glimpse into CB1R Structure: The Second Extracellular Loop (ECL2) as a Significant Region of the CB1 Receptor
8. Allosteric Modulators of CB1R
9. Challenges and Perspectives for Translational Use of CB1R Allosteric Modulators
10. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
CB1R | Cannabinoid receptor type 1 |
GPCR | G protein-coupled receptor |
ECL2 | Extracellular loop 2 |
ECS | Endocannabinoid system |
AEA | Anandamide |
2-AG | 2-Arachidonoylglycerol |
CB2R | Cannabinoid receptor type 2 |
FAAH | Fatty acid amide hydrolase |
MGL | Monoacylglycerol lipase |
NMR | Nuclear magnetic resonance |
EPR | Electron paramagnetic resonance |
MS | Mass spectrometry |
FRET | Fluorescence resonance energy transfer |
X-ray | X-ray crystallography |
IUPHAR | The International Union of Basic and Clinical Pharmacology |
7TMRs | Seven-Transmembrane Receptors |
NALs | Neutral allosteric ligands |
CNR1 | Cannabinoid receptor 1 gene |
kDa | Kilo Dalton |
TMH | Transmembrane-helix |
ICL | Intracellular loop |
∆-9-THC | Delta 9 tetrahydrocannabinol |
CP 55,940 | [2-((1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)-5-(2-methyloctan-2-yl)phenol] |
HU-210 | [(6aR,10aR)-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetra-hydro-6H-benzo[c]chromen-1-ol]- |
WIN 55212-2 | [(R)-(5-methyl-3-(morpholinomethyl)-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indol-6-yl)-(naphthalen-1-yl)methanone] |
JWH-018 | [Naphthalen-1-yl-(1-pentylindol-3-yl)methanone] |
SR-141716A (rimonabant) | [5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide] |
AM251 | [1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidinyl)-1-pyrazole-3-carboxamide] |
AIDS | Acquired immunodeficiency syndrome |
FDA | Food and Drug Administration |
cAMP | Cyclic adenosine monophosphate |
PKA | Protein kinase A |
PKB | Protein kinase B |
MAPKs | Mitogen-activated protein kinases |
ERK | Extracellular signal-regulated protein kinase |
JNK | C-JUN N-terminal kinase |
PI3K | Phosphoinositide 3-kinases |
AP-3 | Adaptor protein 3 |
GASP | GPCR-associated sorting proteins |
FAN | Factor associated with neutral sphingomyelinase activation |
CRIP1a | Cannabinoid receptor-interacting protein 1a |
VGCC | Voltage-gated calcium channel |
GIRK | G-protein-coupled inwardly rectifying potassium channels |
A2A | Adenosine receptor dopamine D2 |
D2 | Dopamine receptor |
CCR2 | Chemokine (C-C motif) receptor type 2 |
CCR9 | Chemokine (C-C motif) receptor type 9 |
β-2AR | Beta-2 adrenergic receptor |
mtCB1 | Mitochondrial cannabinoid receptor |
sAC | Soluble adenylyl cyclase |
MECA | Melanocortin, endothelial differentiation, cannabinoid, adenosine cluster |
AA2AR | adenosine A2A receptor |
CWxP | Cys-Trp-Xaa-Pro motif |
EC | Extracellular |
Cys | Cysteine |
MPR | Membrane proximal region |
Org | Organon |
PAM | Positive allosteric modulator |
NAM | Negative allosteric modulator |
SAR | Structure–activity relationship |
MDMB-Fubinaca | Indazole-based synthetic cannabinoid |
LXA4 | Lipoxin 4 |
CBD | Cannabidiol |
DAT | Dopamine active transporter |
RTI-371 | 3β-(4-Methylphenyl)-2β-[3-(4-chlorophenyl)isoxazol-5-yl]tropane |
7TMR | Seven-Transmembrane Receptors |
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Compound | IUPAC Nomenclature |
---|---|
CP 55,940 | [2-((1R,2R,5R)-5-Hydroxy-2-(3-hydroxypropyl) cyclohexyl)-5-(2-methyloctan-2-yl)phenol] |
HU-210 | [(6aR,10aR)-9-(Hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydro-6H-benzo [c]chromen-1-ol] |
WIN 55212-2 | [(R)-(5-Methyl-3-(morpholinomethyl)-2,3-dihydro-[1,4]oxazino [2,3,4-hi]indol-6-yl)(naphthalen-1-yl)methanone] |
JWH-018 | [Naphthalen-1-yl-(1-pentylindol-3-yl)methanone] |
SR-141716A (rimonabant) | [5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide] |
AM251 | [1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide] |
Human Homo Sapiens (NC_000006.12) vs | CNR1 Gene | ECL2 Region | |
---|---|---|---|
Coverage | Identity | Identity | |
Chimpanzee Pan troglodytes (NC-006473.4) | 99% | 99% | 99% |
Pig Sus scrofa (NC_010443.5) | 56% | 85% | 88% |
House mouse Mus musculus (NC_000070.6) | 29% | 83% | 92% |
Norway rat Rattus norvegicus(NC_005104.4) | 28% | 83% | 92% |
Dog Canis lupus familiaris(NC_030681.1) | 50% | 84% | 92% |
Tropical clawed frog Xenopus tropicalis (NC_030681.1) | 4% | 76% | 78% |
Zebrafish Danio rerio (NC_007131.7) | 3% | 76% | 72% |
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Hryhorowicz, S.; Kaczmarek-Ryś, M.; Andrzejewska, A.; Staszak, K.; Hryhorowicz, M.; Korcz, A.; Słomski, R. Allosteric Modulation of Cannabinoid Receptor 1—Current Challenges and Future Opportunities. Int. J. Mol. Sci. 2019, 20, 5874. https://doi.org/10.3390/ijms20235874
Hryhorowicz S, Kaczmarek-Ryś M, Andrzejewska A, Staszak K, Hryhorowicz M, Korcz A, Słomski R. Allosteric Modulation of Cannabinoid Receptor 1—Current Challenges and Future Opportunities. International Journal of Molecular Sciences. 2019; 20(23):5874. https://doi.org/10.3390/ijms20235874
Chicago/Turabian StyleHryhorowicz, Szymon, Marta Kaczmarek-Ryś, Angelika Andrzejewska, Klaudia Staszak, Magdalena Hryhorowicz, Aleksandra Korcz, and Ryszard Słomski. 2019. "Allosteric Modulation of Cannabinoid Receptor 1—Current Challenges and Future Opportunities" International Journal of Molecular Sciences 20, no. 23: 5874. https://doi.org/10.3390/ijms20235874