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ATP-sensitive potassium (KATP) channels play a prominent role in controlling cardiovascular function. In this paper, a novel series of 4-(1-oxo-2-cyclopentenyl)-1,4-benzothiazine derivatives modified at the C-2, and C-6 positions were synthesized as openers of vascular KATP channels. Most of the tested compounds evoked vasorelaxing effects on rat aortic rings and membrane hyperpolarization in human vascular smooth muscle cells, with potency similar or superior to that of the reference levcromakalim (LCRK). The selective KATP blocker glibenclamide antagonized the above vascular effects, confirming that KATP channels are closely involved in the mechanism of action. The experimental results confirmed the 1,4-benzothiazine nucleus as an optimal scaffold for activators of vascular KATP channels; moreover, the high level of potency exhibited by the 6-acetyl substituted benzothiazine 8, along with the lack of any significant interference with insulin secretion from pancreatic β-cells, paves the way to further develop a new series of potent activators of vascular KATP channels.

Recent years have witnessed a renewed interest in PARP-1 inhibitors as promising anticancer agents with multifaceted functions. Particularly exciting developments include the approval of olaparib (Lynparza) for the treatment of refractory ovarian cancer in patients with BRCA1/2 mutations, and the increasing understanding of the polypharmacology of PARP-1 inhibitors. The aim of this review article is to provide the reader with a comprehensive overview of the distinct levels of the polypharmacology of PARP-1 inhibitors, including 1) inter-family polypharmacology, 2) intra-family polypharmacology, and 3) multi-signaling polypharmacology. Progress made in gaining insight into the molecular basis of these multiple target-independent and target-dependent activities of PARP-1 inhibitors are discussed, with an outlook on the potential impact that a better understanding of polypharmacology may have in aiding the explanation as to why some drug candidates work better than others in clinical settings, albeit acting on the same target with similar inhibitory potency.

Recent years have witnessed a renewed interest in PARP-1 inhibitors as promising anticancer agents with multifaceted functions. Particularly exciting developments include the approval of olaparib (Lynparza) for the treatment of refractory ovarian cancer in patients with BRCA1/2 mutations, and the increasing understanding of the polypharmacology of PARP-1 inhibitors. The aim of this review article is to provide the reader with a comprehensive overview of the distinct levels of the polypharmacology of PARP-1 inhibitors, including 1) inter-family polypharmacology, 2) intra-family polypharmacology, and 3) multi-signaling polypharmacology. Progress made in gaining insight into the molecular basis of these multiple target-independent and target-dependent activities of PARP-1 inhibitors are discussed, with an outlook on the potential impact that a better understanding of polypharmacology may have in aiding the explanation as to why some drug candidates work better than others in clinical settings, albeit acting on the same target with similar inhibitory potency.

γ-Hydroxybutyric acid (GHB) is a therapeutic drug, a drug of abuse, and an endogenous substance that binds to low- and high-affinity sites in the mammalian brain. To target the specific GHB binding sites, we have developed a (125)I-labeled GHB analog and characterized its binding in rat brain homogenate and slices. Our data show that [(125)I]4-hydroxy-4-[4-(2-iodobenzyloxy)phenyl]butanoate ([(125)I]BnOPh-GHB) binds to one site in rat brain cortical membranes with low nanomolar affinity (K(d), 7 nM; B(max), 61 pmol/mg protein). The binding is inhibited by GHB and selected analogs, but not by γ-aminobutyric acid. Autoradiography using horizontal slices from rat brain demonstrates the highest density of binding in hippocampus and cortical regions and the lowest density in the cerebellum. Altogether, the findings correlate with the labeling and brain regional distribution of high-affinity GHB sites or [(3)H](E,RS)-(6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid ([(3)H]NCS-382) binding sites. Using a (125)I-labeled photoaffinity derivative of the new GHB ligand, we have performed denaturing protein electrophoresis and detected one major protein band with an apparent mass of 50 kDa from cortical and hippocampal membranes. [(125)I]BnOPh-GHB is the first reported (125)I-labeled GHB radioligand and is a useful tool for in vitro studies of the specific high-affinity GHB binding sites. The related photoaffinity linker [(125)I]4-hydroxy-4-[4-(2-azido-5-iodobenzyloxy)phenyl]butanoate can be used as a probe for isolation of the elusive GHB binding protein.

International audience; Bile acids regulate nongenomic actions through the activation of TGR5, a membrane receptor that is G protein-coupled to the induction of adenylate cyclase. In this work, a training set of 43 bile acid derivatives is used to develop a molecular interaction field analysis (MFA) and a 3D-quantitative structure-activity relationship study (3D-QSAR) of TGR5 agonists. The predictive ability of the resulting model is evaluated using an external set of compounds with known TGR5 activity, and six bile acid derivatives whose unknown TGR5 activity is herein assessed with in vitro luciferase assay of cAMP formation. The results show a good predictive model and indicate a statistically relevant degree of correlation between the TGR5 activity and the molecular interaction fields produced by discrete positions of the bile acid scaffold. This information is instrumental to extend on a quantitative basis the current structure-activity relationships of bile acids as TGR5 modulators and will be fruitful to design new potent and selective agonists of the receptor.

In 2012, we conducted a retrospective cross-sectional study to assess the number of people living with HIV linked to care and, among these, the number of people on antiretroviral therapy. The health authority in each of the 20 Italian Regions provided the list of Public Infectious Diseases Clinics providing antiretroviral therapy and monitoring people with HIV infection. We asked every Public Infectious Diseases Clinic to report the number of HIV-positive people diagnosed and linked to care and the number of those on antiretroviral therapy during 2012. In 2012, 94,146 people diagnosed with HIV and linked to care were reported. The majority were males (70.1%), Italians (84.4%), and aged between 25 and 49 years (63.4%); the probable route of transmission was heterosexual contact in 37.5% of cases, injecting drug use in 28.1%, and male-to-male contact in 27.9%. Among people in care, 20.1% had less than 350 CD4 cells/μl, 87.6% received antiretroviral therapy, and among these, 62.4% had a CD4 cell count higher than 350 cells/μl. The overall estimated prevalence of individuals diagnosed and linked to care in 2012 in Italy was 0.16 per 100 residents (all ages). Adding the estimated proportion of undiagnosed people, the estimated HIV prevalence would range between 0.19 and 0.26 per 100 residents. In Italy, the majority of people diagnosed and linked to care receive antiretroviral therapy. A higher prevalence of individuals diagnosed and linked to care was observed in Northern Italy and among males. More information for developing the HIV care continuum is necessary to improve the entire engagement in care, focusing on test-and-treat strategies to substantially reduce the proportion of people still undiagnosed or with a detectable viral load.

Grounding on our former 3D QSAR studies, a knowledge-based screen of natural bile acids from diverse animal species has led to the identification of avicholic acid as a selective but weak TGRS agonist. Chemical modifications of this compound resulted in the disclosure of 6 alpha-ethyl-16-epi-avicholic acid that shows enhanced potency at TGRS and FXR receptors. The synthesis, biological appraisals, and structure-activity relationships of this series of compounds are herein described. Moreover, a thorough physicochemical characterization of 6 alpha-ethyl-16-epi-avicholic acid as compared to naturally occurring bile acids is reported and discussed.

A new divergent synthesis of DAF-12 ligands, namely Δ 4 - and Δ 7 -dafachronic acid, is described starting from the natural bile acid hyodeoxycholic acid. Homologation of the side chain followed by stereoselective reduction of the Δ 24 olefinic linkage, 6α-dehydroxylation and C 3 -oxidation affords dafachronic acids in good yields and high diastereoselectivity making this approach easily accessible and scalable.

Gamma-hydroxybutyric acid (GHB) is a psychotropic compound endogenous to the brain. Despite its potential physiological significance, the complete molecular mechanisms of action remain unexplained. To facilitate the isolation and identification of the high-affinity GHB binding site, we herein report the design and synthesis of the first (125)I-labeled radioligands in the field, one of which contains a photoaffinity label which enables it to bind irreversibly to the high-affinity GHB binding sites.

PARP-1 and PARP-2 are members of the family of poly(ADP-ribose)polymerases, which are involved in the maintenance of genomic integrity under conditions of genotoxic stimuli. The different roles of the two isoforms under pathophysiological conditions have not yet been fully clarified, and this is partially due to the lack of selective inhibitors. We report herein the synthesis and preliminary pharmacological evaluation of a large series of isoquinolinone derivatives as PARP-1/PARP-2 inhibitors. Among them, we identified the 5-benzoyloxyisoquinolin-1(2 H)-one derivative as the most selective PARP-2 inhibitor reported so far, with a PARP-2/PARP-1 selectivity index greater than 60.

Activation of poly(ADP-ribose) polymerase (PARP) is an important factor in controlling cell survival or death. As a consequence, therapeutic interventions with PARP-1 inhibitors are sought in different pathological conditions such as cancer, cardiovascular and inflammatory diseases, as well as brain ischemia. In the first part of this work, as a continuation of our efforts in the field, we report the design, synthesis and biological appraisal of novel potent PARP-1 inhibitors. A crystallization experiment is carried out to ascertain the mode of binding to PARP-1 of the most potent compound, namely 2-((dimethylamino)methyl)-9-hydroxythieno[2,3-c]isoquinolin-5(4H)-one (HYDAMTIQ), whilst molecular modeling studies are performed to infer the role of water molecules in ligand binding. In the second part of the work, we discuss the results of HYDAMTIQ in models of brain ischemia as well as its preliminary physicochemical and pharmacokinetic characterization. Collectively, the data obtained qualify HYDAMTIQ as a novel lead candidate for advancement to clinical settings of brain ischemia.