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Cannabinoid subtype 1 receptors (CB1Rs) are an important class of G proteincoupled receptors (GPCRs) belonging to the endocannabinoid system. CB1Rs play a crucial modulatory role in the functioning of other neurotransmitter systems and are involved in a wide range of physiological functions and dysfunctions; thus, they are considered one of the most important targets for drug development, as well as diagnostic purposes. Despite this, only a few molecules targeting this receptor are available on the pharmaceutical market, thus emphasizing the need to gain a deeper understanding of the complex activation pathways of CB1Rs and how they regulate diseases. As part of this review, we provide an overview of pharmacological and imaging tools useful for detecting CB1Rs. Herein, we summarize the derivations of cannabinoids and terpenoids with fluorescent compounds, radiotracers, or photochromic motifs. CB1Rs' molecular probes may be used in vitro and, in some cases, in vivo for investigating and exploring the roles of CB1Rs together with the starting point for the development of CB1R-targeted drugs. [ABSTRACT FROM AUTHOR]

SNAP-tag® is a powerful technology for the labelling of protein/enzymes by using benzyl-guanine (BG) derivatives as substrates. Although commercially available or ad hoc produced, their synthesis and purification are necessary, increasing time and costs. To address this limitation, here we suggest a revision of this methodology, by performing a chemo-enzymatic approach, by using a BG-substrate containing an azide group appropriately distanced by a spacer from the benzyl ring. The SNAP-tag® and its relative thermostable version (SsOGT-H5) proved to be very active on this substrate. The stability of these tags upon enzymatic reaction makes possible the exposition to the solvent of the azide-moiety linked to the catalytic cysteine, compatible for the subsequent conjugation with DBCO-derivatives by azide-alkyne Huisgen cycloaddition. Our studies propose a strengthening and an improvement in terms of biotechnological applications for this self-labelling protein-tag. [ABSTRACT FROM AUTHOR]

Abstract: 12-Phenylacetyl-ricinoleoyl-vanillamide (phenylacetylrinvanil, PhAR, IDN5890), is an ultra-potent agonist of human vanilloid TRPV1 receptors also endowed with moderate affinity for human cannabinoid CB2 receptors. To improve its CB2 affinity and temper its potency at TRPV1, the modification of the polar headgroup and the lipophilic 12-acylgroup of PhAR was pursued. Replacement of the vanillyl headgroup of PhAR with various aromatic or alkyl amino groups decreased activity at TRPV1 receptors, although the dopamine, cyclopropylamine, 1′-(R)- and 1′-(S)-methyl-ethanolamine, and ethanolamine derivatives retained significant potency (EC50 31–126nM). Within these compounds, the 12-phenylacetylricinoleyl cyclopropylamide and ethanolamide were the strongest ligands at CB2 receptors, with K i of 22 and 44nM, and 14- and >20-fold selectivity over cannabinoid CB1 receptors, respectively. The propyl- and allyl-derivatives also exhibited high affinity at CB2 receptors (K i =40 and 22nM, with 40 and >80-fold selectivity over CB1 receptors, respectively), but no activity at TRPV1 receptors. The cyclopropyl- and allyl-derivatives behaved as CB2 inverse agonists in the GTP-γ-S binding assay. Addition of para-methoxy, -tert-butyl or -chlorine groups to the 12-phenylacetyl moiety of PhAR produced compounds that retained full potency at TRPV1 receptors, but with improved selectivity over CB2 or CB1 receptors. Thus, the manipulation of PhAR led to the development of the first CB2/TRPV1 dual ligands and of an entirely new class of inverse agonists at CB2 receptors. Both types of compounds might find application in the treatment of inflammation, and represent new molecular probes to investigate the endocannabinoid–endovanilloid signalling system. [Copyright &y& Elsevier]

Taxanes, mainly paclitaxel and docetaxel, the microtubule stabilizers, have been well known for being the first-line therapy for breast cancer for more than the last thirty years. Moreover, they have been also used for the treatment of ovarian, hormone-refractory prostate, head and neck, and non-small cell lung carcinomas. Even though paclitaxel and docetaxel significantly enhance the overall survival rate of cancer patients, there are some limitations of their use, such as very poor water solubility and the occurrence of severe side effects. However, this is what pushes the research on these microtubule-stabilizing agents further and yields novel taxane derivatives with significantly improved properties. Therefore, this review article brings recent advances reported in taxane research mainly in the last two years. We focused especially on recent methods of taxane isolation, their mechanism of action, development of their novel derivatives, formulations, and improved tumor-targeted drug delivery. Since cancer cell chemoresistance can be an unsurpassable hurdle in taxane administration, a significant part of this review article has been also devoted to combination therapy of taxanes in cancer treatment. Last but not least, we summarize ongoing clinical trials on these compounds and bring a perspective of advancements in this field. [ABSTRACT FROM AUTHOR]

Tropical plants are expected to have a higher variety of defensive traits, such as a more diverse array of secondary metabolic compounds in response to greater pressures of antagonistic interactions, than their temperate counterparts. We test this hypothesis using advanced metabolomics linked to a novel stoichiometric compound classification to analyze the complete foliar metabolomes of four tropical and four temperate tree species, which were selected so that each subset contained the same amount of phylogenetic diversity and evenness. We then built Bayesian phylogenetic multilevel models to test for tropical–temperate differences in metabolite diversity for the entire metabolome and for four major families of secondary compounds. We found strong evidence supporting that the leaves of tropical tree species have a higher phenolic diversity. The functionally closer group of polyphenolics also showed moderate evidence of higher diversity in tropical species, but there were no differences either for the entire metabolome or for the other major families of compounds analyzed. This supports the interpretation that this tropical–temperate contrast must be related to the functional role of phenolics and polyphenolics. [ABSTRACT FROM AUTHOR]