Discriminative stimulus properties of (±)-fenfluramine: The role of 5-HT? receptor subtypes.

The role of serotonin 5-HT? receptors (5-HT?R) in the discriminative stimulus effects of fenfluramine was investigated. Male Sprague-Dawley rats were trained to discriminate (±)-fenfluramine (2 mg/kg ip) from saline using a 2-lever, water-reinforced paradigm. Drug-lever responding after fenfluramine was dose-dependent. The 5-HT2C/1BR agonist mCPP and the 5-HT2CR agonist MK 212 fully substituted, whereas the 5-HT2A/2CR agonist DOI partially substituted, for the training drug. The 5-HT2BR agonist BW 723C86 engendered saline-lever responding. The 5-HT2C/2BR antagonist SB 206553 completely antagonized the fenfluramine discrimination as well as the full substitutions of mCPP and MK 212 and the partial substitution of DOI. The selective 5-HT2AR antagonist M100907 partially suppressed the stimulus effects of fenfluramine, mCPP, and MK 212 and almost fully attenuated the partial substitution of DOI. RS 102221, a selective 5-HT2CR antagonist that does not cross the blood-brain barrier, did not alter the fenfluramine cue. Results demonstrate that the discriminative stimulus effects of fenfluramine are centrally mediated by 5-HT2CR and to some extent by 5-HT2AR. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Enhancement of excessive lever-pressing after post-training signal attenuation in rats by repeated administration of the D? antagonist SCH 23390 or the D? agonist quinpirole, but not the D? agonist SKF 38393 or the D? antagonist haloperidol.

The authors have recently shown that attenuation of an external response feedback leads to excessive lever-pressing that is not associated with attempts to collect reward, and they have suggested that this may be an analogue to unreasonable excessive behavior characteristic of obsessive–compulsive disorder. The present study shows that repeated administration of SCH 23390 or quinpirole, but not SKF 38393 or haloperidol, enhances this behavioral pattern. On the basis of data regarding the enduring effects of chronic treatment with dopaminergic agents, these results suggest that overstimulation of striatal D? receptors underlies enhanced response to signal attenuation. These results may link the hypothesis that obsessions and compulsions result from a deficient response feedback mechanism with findings implicating dopaminergic abnormalities in the production of obsessions and compulsions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Future Prospects of Immunotherapy in Non-Small-Cell Lung Cancer Patients: Is There Hope in Other Immune Checkpoints Targeting Molecules?

Currently, one of the leading treatments for non-small-cell lung cancer is immunotherapy involving immune checkpoint inhibitors. These monoclonal antibodies restore the anti-tumour immune response altered by negative immune checkpoint interactions. The most commonly used immunotherapeutics in monotherapy are anti-PD-1 and anti-PD-L1 antibodies. The effectiveness of both groups of antibodies has been proven in many clinical trials, which have translated into positive immunotherapeutic registrations for cancer patients worldwide. These antibodies are generally well tolerated, and certain patients achieve durable responses. However, given the resistance of some patients to this form of therapy, along with its other drawbacks, such as adverse events, alternatives are constantly being sought. Specifically, new drugs targeting already known molecules are being tested, and new potential targets are being explored. The aim of this paper is to provide an overview of the latest developments in this area.     

Discovery of Small Molecule Activators of Chemokine Receptor CXCR4 That Improve Diabetic Wound Healing

Diabetes produces a chronic inflammatory state that contributes to the development of vascular disease and impaired wound healing. Despite the known individual and societal impacts of diabetic ulcers, there are limited therapies effective at improving healing. Stromal cell-derived factor 1α (SDF-1α) is a CXC chemokine that functions via activation of the CXC chemokine receptor type 4 (CXCR4) receptor to recruit hematopoietic cells to locations of tissue injury and promote tissue repair. The expression of SDF-1α is reduced in diabetic wounds, suggesting a potential contribution to wound healing impairment and presenting the CXCR4 receptor as a target for therapeutic investigations. We developed a high-throughput β-arrestin recruitment assay and conducted structure–activity relationship (SAR) studies to screen compounds for utility as CXCR4 agonists. We identified CXCR4 agonist UCUF-728 from our studies and further validated its activity in vitro in diabetic fibroblasts. UCUF-728 reduced overexpression of miRNA-15b and miRNA-29a, negative regulators of angiogenesis and type I collagen production, respectively, in diabetic fibroblasts. In vivo, UCUF-728 reduced the wound closure time by 36% and increased the evidence of angiogenesis in diabetic mice. Together, this work demonstrates the clinical potential of small molecule CXCR4 agonists as novel therapies for pathologic wound healing in diabetes.     

Identification of estrogen receptor agonists in sediments from Wenyu River, Beijing, China

Assignment of ecological impacts of contamination to specific classes of contaminants is a prerequisite for risk assessment and remediation. In this study, the combination of polarity-based fractionation, two-hybrid yeast bioassay, and chemical analysis were used to evaluate and identify estrogen receptor agonists (ER-agonists) in sediments from Wenyu River, Beijing, China. By bioassay, organic raw sediment extracts could induce significant estrogenicity and the bioassay-derived 17β-estradiol equivalents (EEQs) of raw extracts (EEQ_raws) ranged from 0.8 to 19.8 ng/g dry weight. By polarity-based fractionation, the raw extracts were separated into three fractions, i.e. non-polar, moderately polar, and polar fractions, which were subjected to bioassay and chemical analysis. The highest estrogenicity was observed in the polar fraction, which accounted for more than 78% of the total. The medium polar fraction contains PAHs and OCPs, and the estrogenic activities in this fraction contributed 3%-12% of the total in raw extract. An estrogenic activity of non-polarity fraction was negligible in compare to other two fractions. By chemical analysis and toxic equivalent calculation, major part of the estrogenicity in polar fraction could be attributed to six natural/synthetic estrogens (16%-63%), i.e. 17β-estradiol, estrone, estriol, 17α-ethynylestradiol, diethylstilbestrol, and β-estradiol-17-valerate, and to nonylphenols (26%-55%). The proposed approach has been successfully used for characterization of ER-agonists in this case study.     

In Vitro Effect of Δ9-Tetrahydrocannabinol and Cannabidiol on Cancer-Associated Fibroblasts Isolated from Lung Cancer

There is evidence that demonstrates the effect of cannabinoid agonists inhibiting relevant aspects in lung cancer, such as proliferation or epithelial-to-mesenchymal transition (EMT). Most of these studies are based on evidence observed in in vitro models developed on cancer cell lines. These studies do not consider the complexity of the tumor microenvironment (TME). One of the main components of the TME is cancer-associated fibroblasts (CAFs), cells that are relevant in the control of proliferation and metastasis in lung cancer. In this work, we evaluated the direct effects of two cannabinoid agonists, tetrahydrocannabinol (THC) and cannabidiol (CBD), used alone or in combination, on CAFs and non-tumor normal fibroblasts (NFs) isolated from adenocarcinoma or from healthy lung tissue from the same patients. We observed that these compounds decrease cell density in vitro and inhibit the increase in the relative expression of type 1 collagen (COL1A1) and fibroblast-specific protein 1 (FSP1) induced by transforming growth factor beta (TGFβ). On the other hand, we studied whether THC and CBD could modulate the interactions between CAFs or NFs and cancer cells. We conditioned the culture medium with stromal cells treated or not with THC and/or CBD and cultured A549 cells with them. We found that culture media conditioned with CAFs or NFs increased cell density, induced morphological changes consistent with EMT, inhibited cadherin-1 (CDH1) gene expression, and induced an increase in the relative expression of cadherin-2 (CDH2) and vimentin (VIM) genes in A549 cells. These changes were inhibited or decreased by THC and CBD administered alone or in combination. In another series of experiments, we conditioned culture media with A549 cells treated or not with THC and/or CBD, in the presence or absence of TGFβ. We observed that culture media conditioned with A549 in the presence of TGFβ induced an increase in the expression of COL1A1 and VIM, both in CAFs and in non-tumor NFs. Both THC and CBD ameliorated these effects. In summary, the results presented here reinforce the usefulness of cannabinoid agonists for the treatment of some relevant aspects of lung cancer pathology, and demonstrate in a novel way their possible effects on CAFs as a result of their relationship with cancer cells. Likewise, the results reinforce the usefulness of the combined use of THC and CBD, which has important advantages in relation to the possibility of using lower doses, thus minimizing the psychoactive effects of THC.     

Glycosylated Neurotensin Analogues Exhibit Sub‐picomolar Anticonvulsant Potency in a Pharmacoresistant Model of Epilepsy

The glycosylation of neuroactive peptides is a promising strategy to treat neurological and psychiatric disorders. Herein we investigated the effects of site‐specific glycosylation of neurotensin (NT). The glycosylated analogues have low‐nanomolar affinities and agonist activities toward NTS1, and suppress seizures with sub‐picomolar potency. Our work points to a new research direction of exploring BBB‐permeable NT analogues as potential first‐in‐class antiepileptic drugs.

     

The Tertiary Amine Nitrogen Atom of Piperazine Sulfonamides as a Novel Determinant of Potent and Selective β3‐Adrenoceptor Agonists

Novel compounds were prepared in fair to good yields as human β₃‐adrenoceptor (β₃‐AR) agonists. In particular, aryloxypropanolamines 7 a – d (EC₅₀=0.57–2.1 nM ) and arylethanolamines 12 a , b , e (EC₅₀=6.38–19.4 nM ) were designed to explore the effects of modifications at the right‐hand side of these molecules on their activity as β₃‐AR agonists. Piperidine sulfonamides 15 a – c , e – g (EC₅₀=6.1–36.2 nM ) and piperazine sulfonamide derivatives 20 – 29 (EC₅₀=1.79–49.3 nM ) were examined as compounds bearing a non‐aromatic linker on the right‐ and left‐hand sides of the molecules. Some piperazine sulfonamides were found to be potent and selective β₃‐AR agonists, even if the amine nitrogen atom is tertiary and not secondary, as is the case for all β₃‐AR agonists reported so far. (S)‐3‐{4‐{N‐{4‐{2‐[2‐Hydroxy‐3‐(4‐hydroxyphenoxy)propylamino]ethyl}phenyl}sulfamoyl}phenoxy}propanoic acid ( 7 d ; EC₅₀=0.57 nM ), (R)‐N‐{4‐[2‐(2‐hydroxy‐2‐phenylethylamino)ethyl]phenyl}‐4‐(3‐octylureido)benzenesulfonamide ( 12 e ; EC₅₀=6.38 nM ), (R)‐2‐[1‐(4‐methoxyphenylsulfonyl)piperidin‐4‐ylamino]‐1‐phenylethanol ( 15 f ; EC₅₀=6.1 nM ), and (S)‐4‐{2‐hydroxy‐3‐[4‐(4‐methoxyphenylsulfonyl)piperazin‐1‐yl]propoxy}phenol ( 25 ; EC₅₀=1.79 nM ) were found to be the most potent β₃‐AR agonists of the aryloxypropanolamine, arylethanolamine, piperidine sulfonamide, and piperazine sulfonamide classes, respectively. The two most potent compounds were identified as possible candidates for further development of β₃‐AR agonists useful in the treatment of β₃‐AR‐mediated pathological conditions.