We report an approach for obtaining novel cannabinoid analogs with controllable deactivation and improved druggability. Our design involves the incorporation of a metabolically labile ester group at the 2'-position on a series of (−)-Δ8-THC analogs. We have sought to introduce benzylic substituents alpha to the ester group which affect the half-lives of deactivation through enzymatic activity while enhancing the affinities and efficacies of individual ligands for the CB1 and CB2 receptors. The 1'-(S)-methyl, 1'-gem-dimethyl and 1'-cyclobutyl analogs exhibit remarkably high affinities for both CB receptors. The novel ligands are susceptible to enzymatic hydrolysis by plasma esterases in a controllable manner while their metabolites are inactive at the CB receptors. In further in vitro and in vivo experiments key analogs were shown to be potent CB1 receptor agonists and exhibit CB1-mediated hypothermic and analgesic effects.

Vitamin C (l-ascorbate, AsA) is an essential nutrient required in key metabolic functions in humans and must be obtained from the diet, mainly from fruits and vegetables. Given its importance in human health and plant physiology we sought to examine the role of the ascorbate recycling enzymes monodehydroascorbate reductase (MDHAR) and dehydroascorbate reductase (DHAR) in tomato (Solanum lycopersicum), an economically important fruit crop. Cytosolic-targeted tomato genes Mdhar and Dhar were cloned and over-expressed under a constitutive promoter in tomato var. Micro-Tom. Lines with increased protein levels and enzymatic activity were identified and examined. Mature green and red ripe fruit from DHAR over-expressing lines had a 1.6 fold increase in AsA content in plants grown under relatively low light conditions (150 µmol m−2 s−1). Conversely, MDHAR over-expressers had significantly reduced AsA levels in mature green fruits by 0.7 fold. Neither over-expressing line had altered levels of AsA in foliar tissues. These results underscore a complex regulation of the AsA pool size in tomato.

We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (−)-Δ8-THC analogues encompassing a carboxyester group within the 3-alkyl chain in an effort to explore this novel cannabinergic chemotype for CB receptor binding affinity, in vitro and in vivo potency and efficacy, as well as controlled deactivation by plasma esterases. We have also probed the chain’s polar characteristics with regard to fast onset and short duration of action. Our lead molecule, namely 2-[(6aR,10aR)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-3-yl]-2-methyl-propanoic acid 3-cyano-propyl ester (AM7438), showed picomolar affinity for CB receptors and is deactivated by plasma esterases while the respective acid metabolite is inactive. In further in vitro and in vivo experiments, the compound was found to be a remarkably potent and efficacious CB1 receptor agonist with relatively fast onset/offset of action.

Vitamin C (ascorbate, AsA) is the most abundant water-soluble antioxidant in plants. Ascorbate provides the first line of defense against damaging reactive oxygen species (ROS), and helps protect plant cells from many factors that induce oxidative stress, including wounding, ozone, high salinity, and pathogen attack. Plant defenses against these stresses are also dependent upon jasmonates (JAs), a class of plant hormones that promote ROS accumulation. Here, we review evidence showing that wounding and JAs influence AsA accumulation in various plant species, and we report new data from Arabidopsis and tomato testing the influence of JAs on AsA levels in wounded and unwounded plants. In both species, certain mutations that impair JA metabolism and signaling influence foliar AsA levels, suggesting that endogenous JAs may regulate steady-state AsA. However, the impact of wounding on AsA accumulation was similar in JA mutants and wild type controls, indicating that this wound response does not require JAs. Our findings also indicate that the effects of wounding and JAs on AsA accumulation differ between species; these factors both enhanced AsA accumulation in Arabidopsis, but depressed AsA levels in tomato. These results underscore the importance of obtaining data from more than one model species, and demonstrate the complexity of AsA regulation.

In 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.

BackgroundWhereas testicular metastases are in themselves a rare entity, testicular secondaries from an appendiceal carcinoma have not yet been described. The case also illustrates the diagnostic dilemma of a tumour presenting as epididymo-orchitis.Case presentationThe authors present a case of an appendiceal carcinoma that, two years after radical therapy, manifested as a secondary in the testis. It was misdiagnosed as an epididymo-orchitis and was only revealed through histology.ConclusionsPractitioners need to remember that long-standing testicular inflammation may result form secondary tumours. Even "exotic" primary tumours in the medical history of the patient must give rise to an increased suspicion threshold.

No abstract

No abstract