Synthesis, biological evaluation, and SAR studies of 14β-phenylacetyl substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones derivatives : Ligands with mixed NOP and opioid receptor profile

© 2018 Kumar, Polgar, Cami-Kobeci, Thomas, Khroyan, Toll and Husbands.A series of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydronoroxymorphinone compounds has been synthesized and evaluated for affinity and efficacy for mu (MOP), kappa (KOP), and delta (DOP) opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. The majority of the new ligands displayed high binding affinities for the three opioid receptors, and moderate affinity for NOP receptors. The affinities for NOP receptors are of particular interest as most classical opioid ligands do not bind to NOP receptors. The predominant activity in the [35S]GTPγS assay was partial agonism at each receptor. The results are consistent with our prediction that an appropriate 14β side chain would access a binding site within the NOP receptor and result in substantially higher affinity than displayed by the parent compound naltrexone. Molecular modeling studies, utilizing the recently reported structure of the NOP receptor, are also consistent with this interpretation.Peer reviewedFinal Published versio

Politicization as Signification: Drag Performance as Hermeneutics

Judith Butler’s seminal book, Gender Trouble, categorizes drag performance as indicative example of gender performance. In it, they categorize drag performance along binary lines of gender “opposites”. I argue that Butler’s theory does not hold if the nuance inherent to drag performance is taken into consideration. In examining its complexity, I establish that the artform and its performers are politicized. Through this politicization, I explore how drag performers and drag performance are signified and are able to be understood hermeneutically as a way to expand Butler’s initial theory

The brain decade in debate: II. Panic or anxiety? From animal models to a neurobiological basis

This article is a transcription of an electronic symposium sponsored by the Brazilian Society of Neuroscience and Behavior (SBNeC). Invited researchers from the European Union, North America and Brazil discussed two issues on anxiety, namely whether panic is a very intense anxiety or something else, and what aspects of clinical anxiety are reproduced by animal models. Concerning the first issue, most participants agreed that generalized anxiety and panic disorder are different on the basis of clinical manifestations, drug response and animal models. Also, underlying brain structures, neurotransmitter modulation and hormonal changes seem to involve important differences. It is also common knowledge that existing animal models generate different types of fear/anxiety. A challenge for future research is to establish a good correlation between animal models and nosological classification.Universidade Federal do Paraná Departamento de Farmacologia Laboratório de Fisiologia e Farmacologia do Sistema Nervoso CentralUniversity of Hawaii Department of NeurobiologyUniversity of Hawaii Department of PsychologyUniversidade de São Paulo Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Departamento de PsicobiologiaUniversidade de São Paulo Faculdade de Medicina de Ribeirão Preto Departamento de FisiologiaUniversidade de São Paulo Faculdade de Medicina de Ribeirão Preto Departamento de NeuropsiquiatriaUniversidade Federal de Santa Catarina Departamento de FarmacologiaCentral Nervous System Research Department Sanofi SynthelaboAston University Institute of Pharmaceutical SciencesHoffmann-La Roche Ltd.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de PsicologiaUniversity of Leeds Department of Psychology Ethopharmacology LaboratoryUniversidade Federal do Espírito Santo Centro de Biomedicina Departamento de Ciências FisiológicasUNIFESP, EPM, Depto. de PsicologiaSciEL

Politicization as Signification: Drag Performance as Hermeneutics

Judith Butler’s seminal book, Gender Trouble, categorizes drag performance as indicative example of gender performance. In it, they categorize drag performance along binary lines of gender “opposites”. I argue that Butler’s theory does not hold if the nuance inherent to drag performance is taken into consideration. In examining its complexity, I establish that the artform and its performers are politicized. Through this politicization, I explore how drag performers and drag performance are signified and are able to be understood hermeneutically as a way to expand Butler’s initial theory

A organização logística da seção de educação do Colégio da Polícia Militar "Cel. PM Felippe de Sousa Miranda"

Orientador: Edelvino Razzolini FilhoMonografia (especialização) - Universidade Federal do Paraná, Especialização em Gestão PúblicaInclui referênciasNão inclui resum

Divergence of Threespine Stickleback That Differ in Nuptial Coloration

Recent research has led to a much better understanding of the evolutionary processes that mold and structure variation within and among populations. How populations diverge at the genome-wide level and how polymorphism is maintained within a species, however, remains unclear. We address these questions with two freshwater color morphs, red and black, of the threespine stickleback fish (Gasterosteus aculeatus) from the northwest United States, in which a shift from red to black nuptial coloration occurred in several locations following glacial retreat. We measured phenotypic variation in a suite of traits and used next generation sequencing to characterize within-species and among-morph genetic variation between the two morphs. We found substantial phenotypic and genetic divergence between color morphs, and patterns observed in a third, mixed morph that are likely due to hybridization between anadromous and freshwater stickleback. This work highlights the central role of natural and sexual selection in the evolution of divergence in nature

Supercritical fluid extraction of Eucalyptus globulus bark: a promising approach for triterpenoid production

Eucalyptus bark contains significant amounts of triterpenoids with demonstrated bioactivity, namely triterpenic acids and their acetyl derivatives (ursolic, betulinic, oleanolic, betulonic, 3-acetylursolic, and 3-acetyloleanolic acids). In this work, the supercritical fluid extraction (SFE) of Eucalyptus globulus deciduous bark was carried out with pure and modified carbon dioxide to recover this fraction, and the results were compared with those obtained by Soxhlet extraction with dichloromethane. The effects of pressure (100-200 bar), co-solvent (ethanol) content (0, 5 and 8% wt), and multistep operation were studied in order to evaluate the applicability of SFE for their selective and efficient production. The individual extraction curves of the main families of compounds were measured, and the extracts analyzed by GC-MS. Results pointed out the influence of pressure and the important role played by the co-solvent. Ethanol can be used with advantage, since its effect is more important than increasing pressure by several tens of bar. At 160 bar and 40 degrees C, the introduction of 8% (wt) of ethanol greatly improves the yield of triterpenoids more than threefold

Nicotinic receptors

Regulation of normal or abnormal behaviour is critically controlled by the central serotonergic systems. Recent evidence has suggested that serotonin (5-HT) neurotransmission dysfunction contributes to a variety of pathological conditions, including depression, anxiety, schizophrenia and Parkinson’s disorders. There is also a great amount of evidence indicating that 5-HT signalling may affect the reinforcing properties of drugs of abuse by the interaction and modulation of dopamine (DA) function. This chapter is focused on one of the more addictive drugs, nicotine. It is widely recognised that the effects of nicotine are strongly associated with the stimulatory action it exhibits on mesolimbic DAergic function. We outline the role of 5-HT and its plethora of receptors, focusing on 5-HT2 subtypes with relation to their involvement in the neurobiology of nicotine addiction. We also explore the novel pharmacological approaches using 5-HT agents for the treatment of nicotine dependence. Compelling evidence shows that 5-HT2C receptor agonists may be possible therapeutic targets for smoking cessation, although further investigation is required.peer-reviewe

Orexin Receptor Antagonism: A New Principle in Neuroscience

Orexins are hypothalamic neuropeptides interacting with G-protein coupled receptors in the brain. They play a role in the regulation of sleep–wake cycles in mammals, as suggested by the deficits in orexinergic function that are associated with rodent, canine and human narcolepsy. Selective or dual orexin1-receptor and/or orexin2-receptor antagonists or agonists that cross the blood-brain-barrier (BBB) may be of therapeutic interest for disorders of disturbed arousal and alertness. This article summarizes recent research to identify and characterize orexin receptor antagonists and their therapeutic potential for normalizing sleep in insomnia patients

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

The nociceptin (NOP) receptor is a G-protein-coupled receptor whose natural ligand is the nociceptin/orphanin FQ (N/OFQ) peptide. Evidence from pharmacological studies suggests that the N/OFQ system is implicated in the regulation of several addiction-related phenomena, such as drug intake, withdrawal and relapse. Here, to further explore the role of NOP system in addiction, we used NOP (-/-) rats to study the motivation for cocaine, heroin and alcohol self-administration in the absence of N/OFQ function. Conditioned place preference (CPP) and saccharin (0.2% w/v) self-administration were also investigated. Results showed that NOP (-/-) rats self-administer less cocaine (0.25, 0.125 or 0.5 mg/infusion) both under a Fixed Ratio 1 and a Progressive Ratio schedule of reinforcement compared to wild type (Wt) controls. Consistently, cocaine (10 mg/kg, i.p.) was able to induce CPP in Wt but not in NOP (-/-). When NOP (-/-) rats were tested for heroin (20 μg/infusion) and ethanol (10% v/v) self-administration, they showeda significantly lower drug intake compared to Wt. Conversely, saccharin self-administration was not affected by NOP deletion, excluding the possibility of nonspecific learning deficits or generalized disruption of reward mechanisms in NOP (-/-) rats. These findings were confirmed with pharmacological experiments using two selective NOP antagonists, SB-612111 and LY2817412. Both drugs attenuated alcohol self-administration in Wt rats but not in NOP (-/-) rats. In conclusion, our results demonstrate that genetic deletion of NOP receptors confers resilience to drug abuse and support a role for NOP receptor antagonism as a potential treatment option for drug addiction.Neuropsychopharmacology accepted article preview online, 26 August 2016. doi:10.1038/npp.2016.171