JD5037 (1) is a potent and selective, peripherally acting inverse agonist of the cannabinoid (CB1R) receptor. Peripheral CB1 receptor antagonists/inverse agonists have great potential in the ...treatment of metabolic disorders like type 2 diabetes, obesity, and nonalcoholic steatohepatitis. We report the synthesis of octadeuterated 2H8‐JD5037 (S, S) (8) along with its (S, R) diastereomer (13) from commercially available L‐valine‐d8 starting material. The 2H8‐JD5037 compound will be used to quantitate unlabeled JD5037 during clinical ADME studies and will be used as an LC‐MS/MS bioanalytical standard.
We report the synthesis of octadeuterated 2H8‐JD5037 (S, S) (8) along with its (S, R) diastereomer (13) from commercially available L‐valine‐D8 starting material. The 2H8‐JD5037 compound will be used to quantitate unlabeled JD5037 during clinical ADME studies and will be used as an LC‐MS/MS bioanalytical standard.
Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and ...rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between tumours. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA 'microsatellite instability/CpG island methylation phenotype' transcriptomic subtype, but had distinct mutation, methylation and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates, including HNF4A (hepatocyte nuclear factor 4, alpha), TOMM34 (translocase of outer mitochondrial membrane 34) and SRC (SRC proto-oncogene, non-receptor tyrosine kinase). Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology.
Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS-1, leads to fatal adult-onset pulmonary fibrosis (PF) with no effective treatment. We ...evaluated the role of the endocannabinoid/CB
R system and inducible nitric oxide synthase (iNOS) for dual-target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS-PF patient-derived lung fibroblasts, and bleomycin-induced PF in pale ear mice (HPS1
). We found overexpression of CB
R and iNOS in fibrotic lungs of HPSPF patients and bleomycin-infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin-induced PF. Simultaneous targeting of CB
R and iNOS by MRI-1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI-1867 treatment abrogated bleomycin-induced increases in lung levels of the profibrotic interleukin-11 via iNOS inhibition and reversed mitochondrial dysfunction via CB
R inhibition. Dual inhibition of CB
R and iNOS is an effective antifibrotic strategy for HPSPF.
JD5037 (
1
) is a potent and selective, peripherally acting inverse agonist of the cannabinoid (CB
1
R) receptor. Peripheral CB
1
receptor antagonists/inverse agonists have great potential in the ...treatment of metabolic disorders like type 2 diabetes, obesity and NASH. We report the synthesis of octa-deuterated
2
H
8
-JD5037 (
S
,
S
) (
8
) along with its (
S, R
) diastereomer (
13
) from commercially available L-valine-d
8
starting material. The
2
H
8
-JD5037 compound will be used to quantitate unlabeled JD5037 during clinical ADME studies and will be used as an LC-MS/MS bioanalytical standard.
We report the synthesis of octa-deuterated
2
H
8
-JD5037 (
S
,
S
) (
8
) along with its (
S, R
) diastereomer (
13
) from commercially available L-valine-D8 starting material. The
2
H
8
-JD5037 compound will be used to quantitate unlabeled JD5037 during clinical ADME studies and will be used as an LC-MS/MS bioanalytical standard.
JD5037 (
1
) is a potent and selective, peripherally acting inverse agonist of the cannabinoid (CB
1
R) receptor. Peripheral CB
1
receptor antagonists/inverse agonists have great potential in the ...treatment of metabolic disorders like type 2 diabetes, obesity, and nonalcoholic steatohepatitis. We report the synthesis of octadeuterated
2
H
8
‐JD5037 (
S
,
S
) (
8
) along with its (
S
,
R
) diastereomer (
13
) from commercially available
L
‐valine‐d
8
starting material. The
2
H
8
‐JD5037 compound will be used to quantitate unlabeled JD5037 during clinical ADME studies and will be used as an LC‐MS/MS bioanalytical standard.
Signaling through integral membrane G protein-coupled receptors (GPCRs) is influenced by lipid composition of cell membranes. By using novel high affinity ligands of human cannabinoid receptor CB
, ...we demonstrate that cholesterol increases basal activation levels of the receptor and alters the pharmacological categorization of these ligands. Our results revealed that (2-(6-chloro-2-((2,2,3,3-tetramethylcyclopropane-1-carbonyl)imino)benzodthiazol-3(2H)-yl)ethyl acetate ligand (MRI-2646) acts as a partial agonist of CB
in membranes devoid of cholesterol and as a neutral antagonist or a partial inverse agonist in cholesterol-containing membranes. The differential effects of a specific ligand on activation of CB
in different types of membranes may have implications for screening of drug candidates in a search of modulators of GPCR activity. MD simulation suggests that cholesterol exerts an allosteric effect on the intracellular regions of the receptor that interact with the G-protein complex thereby altering the recruitment of G protein.
Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB
R has been shown to promote both ...processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-α, which has been shown to inhibit insulin signaling in multiple cell types, including hepatocytes. Here, we sought to identify the role of CB
R in KCs in obesity-induced hepatic insulin resistance.
We used intravenously administered β-D-glucan-encapsulated siRNA to knock-down CB
R gene expression selectively in KCs.
We demonstrate that a robust knock-down of the expression of Cnr1, the gene encoding CB
R, results in improved glucose tolerance and insulin sensitivity in diet-induced obese mice, without affecting hepatic lipid content or body weight. Moreover, Cnr1 knock-down in KCs was associated with a shift from pro-inflammatory M1 to anti-inflammatory M2 cytokine profile and improved insulin signaling as reflected by increased insulin-induced Akt phosphorylation.
These findings suggest that CB
R expressed in KCs plays a critical role in obesity-related hepatic insulin resistance via a pro-inflammatory mechanism.
JD5037 (1) is a potent and selective, peripherally acting inverse agonist of the cannabinoid (CB
R) receptor. Peripheral CB
receptor antagonists/inverse agonists have great potential in the treatment ...of metabolic disorders like type 2 diabetes, obesity, and nonalcoholic steatohepatitis. We report the synthesis of octadeuterated
H
-JD5037 (S, S) (8) along with its (S, R) diastereomer (13) from commercially available L-valine-d
starting material. The
H
-JD5037 compound will be used to quantitate unlabeled JD5037 during clinical ADME studies and will be used as an LC-MS/MS bioanalytical standard.
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