Global ETD Search

31	Models for predicting efflux transport over the blood-brain barrier Janani, Marjaneh January 2020 (has links) Aim: The general aim of this research is development and evaluation of novel methods for predicting active transport over the human blood-brain-barrier (BBB), while this project specifically aims to i) review the literature and select suitable methods and substrates, ii) develop models for determining in vitro kinetic properties of selected compounds, analyze the in vitro data using the developed models and to use Maximum Transport Activity (MTA) approach (Karlgren et al., 2012), iii) perform Physiology Based Pharmacokinetic (PBPK) modelling and compare to in vivo literature data. Background: Drug permeation to the brain through blood circulation is primarily limited by blood-brain barrier (BBB), due to existence of tight junctions in endothelial cells of blood vessels as well as active efflux and influx transporters in the barrier. Toxicity and CNS related side effects can be caused by peripheral targeted drugs crossing BBB. Hence, prediction of BBB permeability and estimation of drug concentration in the brain tissue are challenging in drug discovery. To resolve this, estimating the human BBB permeability using improved in vitro and in silico predictive models can be a facilitator. Methods: In vitro data provided by the Drug Delivery research group was used to develop in vitro predictive models for BBB penetration of Verapamil, Risperidone, and Prazosin using R-studio 1.2.5. The MTA approach was adjusted for extrapolation of BBB in vitro transporter activity to in vivo condition. For PBPK modelling, we took advantage of PK-Sim® to simulate drug disposition and time profile of Risperidone in human and animal species. Results: It was shown that MDR1 is the major transporter for efflux transport of Prazosin and Risperidone in brain while both BCRP and MDR1 have similar impact on transport of Verapamil. Furthermore, it was presented in PBPK models that the predicted brain concentration of Risperidone increases in rat and nonhuman primate (NHP) when MDR1 And BCRP are knocked out while the brain concentration of Risperidone in dog is not affected by expression level of the efflux transporters. Conclusion: Both MDR1 and BCRP are contributing in efflux transport of Verapamil, Risperidone, and Prazosin across the BBB. Additionally, expression of the efflux transporters shown to have an impact on brain exposure of Risperidone in animal PBPK models. efflux transport brain blood-brain-barrier Verapamil Risperidone Prazosin Medical and Health Sciences Medicin och hälsovetenskap Pharmaceutical Sciences Farmaceutiska vetenskaper
32	Differential Pharmacological Profiles of Operant Acquisition, Operant Expression, and Decision-Making Performance As Tested By Antipsychotics and Other Dopaminergic Drugs Baker, Tyson 15 March 2013 (has links) Operant acquisition, operant expression, and decision-making differentially rely on brain areas that are differentially affected by antipsychotic and other dopaminergic drugs. The purpose of this thesis was to test if the known differential pharmacological and location of action of antipsychotic and other dopaminergic drugs predict the drug effects on operant acquisition, operant expression, and decision-making. Clozapine and to a lesser extent, risperidone but not metoclopramide or haloperidol affect the prefrontal cortex (PFC); haloperidol, metoclopramide, and to a lesser extent, risperidone affect the dorsolateral striatum (DLS). We used amphetamine as a broadly-acting indirect dopamine (DA), serotonin (5-HT), and norepinephrine agonist. We found that all antagonists altered operant acquisition and expression, but in different ways. The DA D2-like receptor antagonists blunted reinforcement impact during operant acquisition and induced an extinction-like decline in expression whereas the atypical antipsychotics with high PFC 5-HT-2A affinity maintained inactive lever presses during acquisition, but produced tolerance in expression. Curiously, risperidone and metoclopramide, but not clozapine or haloperidol, more potently suppressed lever pressing in acquisition than expression. In contrast, amphetamine suppressed operant expression, but not acquisition, at a dose range that increased locomotion and induced conditioned place preference. Amphetamine decreased sensitivity to reward presentation and inactive lever pressing during operant acquisition, but had the opposite effects during expression. A very different pattern was found in the rodent gambling task (rGT), a model of the 4- choice (deck) Iowa Gambling Task used in humans. The rGT puts small, immediate rewards that are advantageous in the long-term due to generally fewer and shorter associated penalties in conflict with large, immediate rewards that are disadvantageous in the long-term due to generally more and longer associated penalties. Two antipsychotics (risperidone, haloperidol) but not the anti-emetic (metoclopramide) enhanced performance by shifting preferences towards advantageous options, but the antipsychotic that induces PFC Fos (clozapine) impaired performance. Amphetamine decreased discrimination among different decks in the rGT. These data demonstrate the differential effects of clinically relevant drugs on decision-making and different stages of operant learning. The differential effects on operant responding and decision-making of different antipsychotic drugs provide important information regarding their therapeutic and side-effect profiles. / Thesis (Ph.D, Psychology) -- Queen's University, 2013-03-14 16:12:57.629 Operant Acquisition Iowa Gambling Task Dopamine Decision-Making Antipsychotic Amphetamine Rodent Gambling Task Haloperidol Risperidone Operant Expression Metoclopramide Clozapine Instrumental Incentive Learning Reinforcement Blunting Operant
33	Homology modeling and structural analysis of the antipsychotic drugs receptorome López Muñoz, Laura 22 June 2010 (has links) Classically it was assumed that the compounds with therapeutic effect exert their action interacting with a single receptor. Nowadays it is widely recognized that the pharmacological effect of most drugs is more complex and involves a set of receptors, some associated to their positive effects and some others to the side effects and toxicity. Antipsychotic drugs are an example of effective compounds characterized by a complex pharmacological profile binding to several receptors (mainly G protein-coupled-receptors, GPCR). In this work we will present a detailed study of known antipsychotic drugs and the receptors potentially involved in their binding profile, in order to understand the molecular mechanisms of the antipsychotic pharmacologic effects.The study started with obtaining homology models for all the receptors putatively involved in the antipsychotic drugs receptorome, suitable for building consistent drug-receptor complexes. These complexes were structurally analyzed and compared using multivariate statistical methods, which in turn allowed the identification of the relationship between the pharmacological properties of the antipsychotic drugs and the structural differences in the receptor targets. The results can be exploited for the design of safer and more effective antipsychotic drugs with an optimum binding profile. / Tradicionalmente se asumía que los fármacos terapéuticamente efectivos actuaban interaccionando con un único receptor. Actualmente está ampliamente reconocido que el efecto farmacológico de la mayoría de los fármacos es más complejo y abarca a un conjunto de receptores, algunos asociados a los efectos terapéuticos y otros a los secundarios y toxicidad. Los fármacos antipsicóticos son un ejemplo de compuestos eficaces que se caracterizan por unirse a varios receptores simultáneamente (principalmente a receptores unidos a proteína G, GPCR). El trabajo de la presente tesis se ha centrado en el estudio de los mecanismos moleculares que determinan el perfil de afinidad de unión por múltiples receptores de los fármacos antipsicóticos.En primer lugar se construyeron modelos de homología para todos los receptores potencialmente implicados en la actividad farmacológica de dichos fármacos, usando una metodología adecuada para construir complejos fármaco-receptor consistentes. La estructura de estos complejos fue analizada y se llevó a cabo una comparación mediante métodos estadísticos multivariantes, que permitió la identificación de asociaciones entre la actividad farmacológica de los fármacos antipsicóticos y diferencias estructurales de los receptores diana. Los resultados obtenidos tienen interés para ser explotados en el diseño de fármacos antipsicóticos con un perfil farmacológico óptimo, más seguros y eficaces. Receptor 5-HT2A Receptor D3 Receptor D2 Ligando Clozapina Derivados Benzofuranonas Risperidona Olanzapina esquizofrenia métodos de regresión campos de interacción Molecular (MIF) Perfil Multireceptorial modelado por homología Docking sitio de unión interacciones moleculares selectividad afinidad de unión Diana Meta-Diana efectos secundarios fármaco antipsicótico típico fármaco antipsicótico atípico agonista antagonista membrana receptoroma rhodopsina estructura de rayos X descriptores moleculares farmacología análisis multivariante procedimiento integrado Computer-aided drug design Integrated approach Multivariate analysis Pharmacology Molecular descriptors X-ray structure Rhodopsin Receptorome Membrane Antagonist Agonist Atypical antipsychotic drug Typical antipsychotic drug Side effects Off-target Target Selectivity Binding affinity Molecular interactions Binding site Homology modeling Docking Multireceptor profile Molecular interaction Field (MIF) Partial Least Squares (PLS) Principal Component Analysis (PCA) Schizophrenia Benzolactam Derivatives Benzofuranone Derivatives Risperidone Olanzapine Clozapine Ligand Adrenergic receptors Muscarinic receptors Histamine receptors Serotonin receptors Dopamine receptors beta2-Adrenergic receptor D2 receptor D3 receptor 5-HT2A receptor G protein-coupled receptors (GPCR) 57

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