The Highs and Lows of Cannabinoid Receptor Expression in Disease: Mechanisms and Their Therapeutic Implications

Miller, Lydia; Devi, Lakshmi A.

doi:10.1124/pr.110.003491

Cited by 159 publications

(128 citation statements)

References 84 publications

(128 reference statements)

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“…k off values were assumed to be 10 h −1 . The drug dose was scaled linearly for the CB1 K D value and was administered every 24 h. R tot,cer,CB1 = 527 nM, R tot,cer,mGlu5 = 5.1 nM, R tot,cer,TRPV1 = 19 nM, R tot,cer,5-HT1a = 0.01, R tot,hyp,CB1 = 248 nM, R tot,hyp,mGlu5 = 16 nM, R tot,hyp,TRPV1 = 13 nM, R tot,hyp,5-HT1a = 2.37, R tot,fc,CB1 = 529 nM, R tot,fc,mGlu5 = 25 nM, R tot,fc,TRPV1 = 12 nM, R tot,fc,5-HT1a = 1.7 nM which is important for the translation from healthy volunteers to patients (24,(66)(67)(68). Finally, it should be considered that there is an increased interest towards allosteric modulation in CNS drug discovery due to the potential benefits with regard to selectivity and side effects (69).…”

Section: Discussionmentioning

confidence: 99%

“…An example of the latter system is the cannabinoid system, of which the cannabinoid receptor CB1 is a major component. The CB1 receptor is widely expressed throughout the body but mainly found in the brain where it mediates a broad range of effects in health and disease (23,24). Many off-targets have been identified for CB1 ligands, including the vanilloid receptor TRPV1, the metabotropic glutamate receptor mGlu5, and the serotonin receptor 5-HT1a (25,26).…”

Section: Introductionmentioning

confidence: 99%

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Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling

Vlot

Witte

Danhof

et al. 2017

AAPS J

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Abstract.Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D ) and the target dissociation rate constant on target and tissue selectivity. The K D values of CB1 ligands in the ChEMBL database are predicted by QSAR random forest (RF) modeling for the CB1 receptor and known off-targets (TRPV1, mGlu5, 5-HT1a). Of these CB1 ligands, rimonabant, CP-55940, and Δ 8 -tetrahydrocanabinol, one of the active ingredients of cannabis, were selected for simulations of target occupancy for CB1, TRPV1, mGlu5, and 5-HT1a in three brain regions, to illustrate the principles of the combined PBPK-QSAR modeling. Our combined PBPK and target binding modeling demonstrated that the optimal values of the K D and k off for target and tissue selectivity were dependent on target concentration and tissue distribution kinetics. Interestingly, if the target concentration is high and the perfusion of the target site is low, the optimal K D value is often not the lowest K D value, suggesting that optimization towards high drug-target affinity can decrease the benefit-risk ratio. The presented integrative structure-pharmacokineticpharmacodynamic modeling provides an improved understanding of tissue and target selectivity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling

Vlot

Witte

Danhof

et al. 2017

AAPS J

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“…The CB1 receptor (CB1R) is highly expressed not only in the CNS but also in peripheral organs (Miller and Devi 2011). In contrast, the CB2 receptor (CB2R) is mainly expressed in the peripheral immune system, including T cells, macrophages, and B cells (Miller and Devi 2011).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect Is Driven Through the Upregulation of CB1 Receptor in Experimental Autoimmune Encephalomyelitis

Lou

Chen

et al. 2015

J Mol Neurosci

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During immuno-mediated demyelinating lesions, endocannabinoid system participates in both inflammatory and neurodegenerative damage through several mechanisms that involve neuronal and immune cells. Here, we constructed lentiviral vector to upregulate CB1 receptor (CB1R) in the lumbar spinal cord 5-6 region and observe the effect of clinical score and possible mechanism on the occurrence and development of experimental autoimmune encephalomyelitis (EAE). The results show that overexpression of CB1R delayed the onset of clinical signs and ameliorated the severity of disease. Overexpression of CB1R significantly inhibited the expression of NF-kB/p65 and TLR-4 as well as levels of IL-1β, IL-6, and TNF-α, followed by a decrease of IL-17 and an increase of IL-10 in the spinal cord of mice. The percentage of M1 marker CD11b(+)CD16/32(+) cells was decreased, while the percentage of M2 marker CD11b(+)CD206(+) and CD11b(+)IL-10(+) cells was elevated in splenic mononuclear cells (MNCs) of mice with overexpression of CB1R. Interestingly, overexpression of CB1R dramatically enhanced the expression of neurotrophic NT-3, BDNF, and GDNF in the spinal cord. These results indicate that local overexpression of CB1R in the spinal cord exhibited neuroprotective effects in EAE, mainly suppressing inflammatory microenvironment and elevating neurotrophic factors, slightly declining IL-1β and IL-17 in the spleen, and increased IL-10 in the brain. Its complexity remains to be carefully considered and further studied in further investigation.

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“…Endocannabinoids are endogenously formed from membrane phospholipids in response to increases in intracellular calcium; they are immediately released and act as ligands of cannabinoid receptors (Miller and Devi 2011). The first endogenous ligand, n-arachidonoylethanolamine, was identified in 1992 from porcine brain (Devane et al 1992).…”

Section: The Endocannabinoid System and Classification Of Cannabinoidsmentioning

confidence: 99%

The use of cannabinoids in animals and therapeutic implications for veterinary medicine: a review

Landa¹,

Šulcová²,

Gbelec³

2016

Vet. Med. - Czech

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Cannabinoids/medical marijuana and their possible therapeutic use have received increased attention in human medicine during the last years. This increased attention is also an issue for veterinarians because particularly companion animal owners now show an increased interest in the use of these compounds in veterinary medicine. This review sets out to comprehensively summarise well known facts concerning properties of cannabinoids, their mechanisms of action, role of cannabinoid receptors and their classification. It outlines the main pharmacological effects of cannabinoids in laboratory rodents and it also discusses examples of possible beneficial use in other animal species (ferrets, cats, dogs, monkeys) that have been reported in the scientific literature. Finally, the article deals with the prospective use of cannabinoids in veterinary medicine. We have not intended to review the topic of cannabinoids in an exhaustive manner; rather, our aim was to provide both the scientific community and clinical veterinarians with a brief, concise and understandable overview of the use of cannabinoids in veterinary medicine.

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The Highs and Lows of Cannabinoid Receptor Expression in Disease: Mechanisms and Their Therapeutic Implications

Cited by 159 publications

References 84 publications

Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling

Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling

Neuroprotective Effect Is Driven Through the Upregulation of CB1 Receptor in Experimental Autoimmune Encephalomyelitis

The use of cannabinoids in animals and therapeutic implications for veterinary medicine: a review

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