Background: Cannabis use suppresses the endocannabinoid system in healthy individuals. However, the association between cannabis use with the endocannabinoid system is understudied in individuals with psychosis despite the high rate of cannabis use in these individuals.
Methods: We enrolled 83 individuals who were admitted to an inpatient psychiatric unit with psychotic presentations, and measured their plasma levels of main endocannabinoids, Anandamide (AEA) and 2-Acylglycerol (2-AG), and endocannabinoid related compounds, Palmitoylethanolamine, and N-oleoylethanolamine.
The antimicrobial resistance crisis requires the introduction of novel antibiotics. The use of conventional broad-spectrum compounds selects for resistance in off-target pathogens and harms the microbiome. This is especially true for Mycobacterium tuberculosis, where treatment requires a 6-month course of antibiotics.
View Article and Find Full Text PDFParkinson's disease (PD) is a progressive neurodegenerative disease, causing loss of motor and nonmotor function. Diagnosis is based on clinical symptoms that do not develop until late in the disease progression, at which point the majority of the patients' dopaminergic neurons are already destroyed. While many PD cases are idiopathic, hereditable genetic risks have been identified, including mutations in the gene for LRRK2, a multidomain kinase with roles in autophagy, mitochondrial function, transcription, molecular structural integrity, the endo-lysosomal system, and the immune response.
View Article and Find Full Text PDFGadolinium is a paramagnetic relaxation enhancement (PRE) agent that accelerates the relaxation of metabolite nuclei. In this study, we noted the ability of gadolinium to improve the sensitivity of two-dimensional, non-uniform sampled NMR spectral data collected from metabolomics samples. In time-equivalent experiments, the addition of gadolinium increased the mean signal intensity measurement and the signal-to-noise ratio for metabolite resonances in both standard and plasma samples.
View Article and Find Full Text PDFFine-tuning than complete disruption of 2-arachidonoylglycerol (2-AG) metabolism in the brain represents a promising pharmacological approach to limit potential untoward effects associated with complete blockade of monoacylglycerol lipase (MGL), the primary hydrolase of 2-AG. This could be achieved through a/b-hydrolase domain containing 6 (ABHD6) inhibition, which will provide a smaller and safer contribution to 2-AG regulation in the brain. Pharmacological studies with ABHD6 inhibitors have recently been reported, where modulation of ABHD6 activity either through CB1R-dependent or CB1R-independent processes showed promise in preclinical models of epilepsy, neuropathic pain and inflammation.
View Article and Find Full Text PDF-Acylethanolamines are signaling lipid molecules implicated in pathophysiological conditions associated with inflammation and pain. -Acylethanolamine acid amidase (NAAA) favorably hydrolyzes lipid palmitoylethanolamide, which plays a key role in the regulation of inflammatory and pain processes. The synthesis and structure-activity relationship studies encompassing the isothiocyanate pharmacophore have produced potent low nanomolar inhibitors for hNAAA, while exhibiting high selectivity (>100-fold) against other serine hydrolases and cysteine peptidases.
View Article and Find Full Text PDFAdamantyl groups are key structural subunit commonly used in many marketed drugs targeting diseases ranging from viral infections to neurological disorders. The metabolic disposition of adamantyl compounds has been mostly studied using LC-MS based approaches. However, metabolite quantities isolated from biological preparations are often insufficient for unambiguous structural characterization by NMR.
View Article and Find Full Text PDFAn amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDFN-acylethanolamine acid amidase (NAAA) inhibition represents an exciting novel approach to treat inflammation and pain. NAAA is a cysteine amidase which preferentially hydrolyzes the endogenous biolipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA is an endogenous agonist of the nuclear peroxisome proliferator-activated receptor-α (PPAR-α), which is a key regulator of inflammation and pain.
View Article and Find Full Text PDFThe current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds. As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s.
View Article and Find Full Text PDFMonoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2.
View Article and Find Full Text PDFThe synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analogue, namely, (13 S,1' R)-dimethylanandamide (AMG315, 3a), a high affinity ligand for the CB1 receptor ( K of 7.8 ± 1.
View Article and Find Full Text PDFNew oximes short-acting CB1 agonists were explored by the introduction of an internal oxime and polar groups at the C3 alkyl tail of Δ-THC. The scope of the research was to drastically alter two important physicochemical properties hydrophobicity (log P) and topological surface area (tPSA) of the compound, which play a critical role in tissue distribution and sequestration (depot effect). Key synthesized analogs demonstrated sub-nanomolar affinity for CB1, marked reduction in hydrophobicity (ClogP∼2.
View Article and Find Full Text PDFIn pursuit of safer controlled-deactivation cannabinoids with high potency and short duration of action, we report the design, synthesis, and pharmacological evaluation of novel C9- and C11-hydroxy-substituted hexahydrocannabinol (HHC) and tetrahydrocannabinol (THC) analogues in which a seven atom long side chain, with or without 1'-substituents, carries a metabolically labile 2',3'-ester group. Importantly, in vivo studies validated our controlled deactivation approach in rodents and non-human primates. The lead molecule identified here, namely, butyl-2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl]-2-methylpropanoate (AM7499), was found to exhibit remarkably high in vitro and in vivo potency with shorter duration of action than the currently existing classical cannabinoid agonists.
View Article and Find Full Text PDFRecent Pat Biotechnol
March 2009
Hemoglobin, the protein responsible for the red color of blood plays a very important part in 'life'- it transports oxygen, without which humans cannot survive. The idea of using purified Hemoglobin as a possible universal substitute for red blood cells has been around for almost a century. Hemoglobin formulations have important therapeutic applications, especially in case of trauma and war when requirements for blood may be very large.
View Article and Find Full Text PDF