Medicinal and Pharmaceutical Chemistry Commons^™

Role Of Medial Prefrontal Cortical Group Ii Metabotropic Glutamate Receptor In The Development Of Cocaine Sensitization, Xiaohu Xie

Theses and Dissertations (ETD)

The current studies examined the role of medial prefrontal cortical (mPFC) group II metabotropic glutamate receptors (mGluR_2/3) in the development of cocaine sensitization. Initial studies demonstrated that intra-mPFC injection of the mGluR_2/3 receptor agonist, APDC, dose-dependently reduced acute behavioral response to cocaine (0.015-15 nmol/side with significant effects starting at 1.5nmol/side). The effects of APDC were prevented by intra-mPFC co-injections of an mGluR_2/3 antagonist, LY341495 (1.5 nmol/side). Repeated intra-mPFC APDC (1.5 nmol/side) injections also prevented the initiation of behavioral and neurochemical sensitization, which is defined as enhanced nucleus accumbens (NAc) dopamine response to cocaine. Once sensitization was …

A Role For Shps-1/Sirpα In Concanavalin A-Dependent Production Of Mmp-9, Arm R. Amin, M. Helal Uddin Biswas, Takeshi Senga, Gen-Sheng Feng, Reiji Kannagi, Munna L. Agarwal, Michinari Hamaguchi

Pharmaceutical Science and Research

SHPS‐1/SIRPα1 is a transmembrane glycoprotein that belongs to the immunoglobulin (Ig) super family. In the present study, we show that SHPS‐1 strongly associates with Concanavalin A (Con A), a plant lectin obtained from jack beans. Further studies with SHPS‐1 mutants reveal that the extracellular domain of SHPS‐1 containing the Ig sequence is responsible for its association with Con A. Con A treatment induces cross‐linking and multimerization of the SHPS‐1 protein in the plasma membrane, accompanied by its tyrosine phosphorylation and recruitment of SHP‐2. In contrast, Ricinus communis agglutinin (RCA), another lectin obtained from castor bean, does not bind or activate …

A Protein Interaction Map Of The Mitotic Spindle, Jonathan Wong, Yuko Nakajima, Stefan Westermann, Ching Shang, Jung-Seog Kang, Crystal Goodner, Pantea Houshmand, Stanley Fields, Clarence S.M. Chan, David Drubin, Georjana Barnes, Tony R. Hazbun

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

The mitotic spindle consists of a complex network of proteins that segregates chromosomes in eukaryotes. To strengthen our understanding of the molecular composition, organization, and regulation of the mitotic spindle, we performed a system-wide two-hybrid screen on 94 proteins implicated in spindle function in Saccharomyces cerevisiae. We report 604 predominantly novel interactions that were detected in multiple screens, involving 303 distinct prey proteins. We uncovered a pattern of extensive interactions between spindle proteins reflecting the intricate organization of the spindle. Furthermore, we observed novel connections between kinetochore complexes and chromatin-modifying proteins and used phosphorylation site mutants of NDC80/TID3 to gain …

Trypanothione Reductase: A Viable Chemotherapeutic Target For Antitrypanosomal And Antileishmanial Drug Design, M. O. Faruk Khan

Pharmaceutical Science and Research

Trypanosomiasis and leishmaniasis are two debilitating disease groups caused by parasites of Trypanosoma and Leishmania spp. and affecting millions of people worldwide. A brief outline of the potential targets for rational drug design against these diseases are presented, with an emphasis placed on the enzyme trypanothione reductase. Trypanothione reductase was identified as unique to parasites and proposed to be an effective target against trypanosomiasis and leishmaniasis. The biochemical basis of selecting this enzyme as a target, with reference to the simile and contrast to human analogous enzyme glutathione reductase, and the structural aspects of its active site are presented. The …

Tobramycin-Induced Hepatotoxicity, Sarah A. Nisly, Shaunta' M. Ray, Robert A. Moye

Scholarship and Professional Work – COPHS

OBJECTIVE. To report a case of tobramycin-induced hepatotoxicity. CASE

SUMMARY: A 20-year-old female was hospitalized for treatment of Pseudomonas aeruginosa bacteremia and osteomyelitis. Empiric intravenous antibiotic therapy with piperacillin/tazobactam, vancomycin, and ciprofloxacin was started, and based on the results of culture and sensitivity testing, was changed to intravenous ceftazidime and tobramycin 70 mg every 8 hours on hospital day 3. Liver enzyme levels then increased over days 3–6. Tests for hepatitis A, B, and C were all nonreactive, and HIV testing was negative. On day 8, therapy was changed from ceftazidime to piperacillin/tazobactam and the tobramycin dose was increased …

Antitrypanosomal, Antileishmanial, And Antimalarial Activities Of Quaternary Arylalkylammonium 2-Amino-4-Chlorophenyl Phenyl Sulfides, A New Class Of Trypanothione Reductase Inhibitor, And Of N-Acyl Derivatives Of 2-Amino-4-Chlorophenyl Phenyl Sulfide, Seheli Parveen, M. O. Faruk Khan, Susan E. Austin, Simon L. Croft, Vanessa Yardley, Peter Rock, Kenneth T. Douglas

Pharmaceutical Science and Research

Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition ∼40-fold (3′,4′-dichlorobenzyl-[5-chloro-2-phenylsulfan- ylphenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive Ki value of 1.7 ( 0.2 µM). Molecular modelling explained docking orientations and energies by: (i) involvement of the Z-site hydrophobic pocket (roughly bounded by F396′, P398′, and L399′), (ii) ionic interactions for the cationic nitrogen with Glu-466′ or -467′. A series of N-acyl-2-amino-4-chlorophenyl sulfides showed mixed inhibition (Ki, Ki′ ) 11.3-42.8 µM). The quaternized analogues of the 2-chlorophenyl phenylsulfides had strong antitrypanosomal and antileishmanial activity in vitro against T. bruceirhodesiense STIB900, …

Probing Proteinase Active Sites Using Oriented Peptide Mixture Libraries – Adam-10, John L. Krstenansky, Jihong Wang, Gregg R. Chenail, Matthew R. Tiffany, Geoffrey M. Kuesters, Barbara C. Natke, John L. Nestor Jr.

Pharmaceutical Science and Research

Oriented Peptide Mixture Libraries can provide a full matrix of preferred and disfavored amino acids at each subsite of an optimal substrate for a new proteinase. This approach is rapid and convenient, requiring only two mixture libraries to complete the analysis. In this paper we demonstrate an extension of this type of analysis, using a focused library employing unnatural amino acids to probe the depth of the S1 position in the catalytic site of the alpha secretase ADAM-10. This analysis indicates that ADAM- 10 will accept amino acids with substantial length and hydrophobicity (e.g. 2- naphthylalanine), but suggests that the …

Riboflavin Synthase Of Schizosaccharomyces Pombe. Protein Dynamics Revealed By 19f Nmr Protein Perturbation Experiments., Markus Fischer, Ann-Kathrin Schott, Kristina Kemter, Richard Feicht, Gerald Richter, Boris Illarionov, Wolfgang Eisenreich, Stefan Gerhardt, Mark S. Cushman, Stefan Steinbacher, Robert Huber, Adelbert Bacher

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Background

Riboflavin synthase catalyzes the transformation of 6,7-dimethyl-8-ribityllumazine into riboflavin in the last step of the riboflavin biosynthetic pathway. Gram-negative bacteria and certain yeasts are unable to incorporate riboflavin from the environment and are therefore absolutely dependent on endogenous synthesis of the vitamin. Riboflavin synthase is therefore a potential target for the development of antiinfective drugs.

Results

A cDNA sequence from Schizosaccharomyces pombe comprising a hypothetical open reading frame with similarity to riboflavin synthase of Escherichia coli was expressed in a recombinant E. coli strain. The recombinant protein is a homotrimer of 23 kDa subunits as shown by sedimentation equilibrium …

Effects Of Mtad On Some Physical Properties Of Enamel And Dentin, Tanya Kristina Machnick

Loma Linda University Electronic Theses, Dissertations & Projects

Recently, a Mixture of Tetracycline, an Acid, and a Detergent (MTAD) has been advocated to remove smear layer and disinfect canals. The purpose of this study was to evaluate the effect of MTAD the flexural strength and modulus of elasticity of dentin as well as its effect on the bond strength to enamel and dentin. In Part I, dentin bars were randomly assigned to eight groups treated either with various concentrations of NaOCl (5.25%, 2.65%, 1.31%, 0.66%), 17% EDTA, MTAD, saline, or according to a clinical protocol with 1.3% NaOCl and then 5 min of MTAD. …

A Study Of 5-Aminolevulinic Acid And Its Methyl Ester Used In In Vitro And In Vivo Systems Of Human Bladder Cancer, Vanaja Manivasager, Paul Wan Sia Heng, Jinsong Hao, Wei Zheng, Khee Chee Soo, Malini Olivo

Pharmaceutical Science and Research

The use of 5-aminolevulinic acid and its esters to induce endogenous porphyrins for the purpose of detection of epithelial cancers is being studied extensively in many centres around the world. The challenge is to prepare an efficacious formulation for the purpose of cancer detection. Photodynamic diagnosis of cancer using 5-aminolevulinic acid (ALA) and its ester derivatives is being actively investigated. In this study, we compared ALA with ALA methyl ester (AME) derivative in terms of PpIX fluorescence intensity in in vitro and in vivo systems of bladder carcinoma. For the in vivo system consisting of RT112 xenografts, the modes of …

Macro-Microscopic Fluorescence Imaging Of Human Npc Xenografts In A Murine Model Using Topical Vs. Intravenous Administration Of 5-Aminolevulinic Acid, Vanaja Manivasager, Paul Wan Sia Heng, Jinsong Hao, Wei Zheng, Khee Chee Soo, Malini Olivo

Pharmaceutical Science and Research

The use of 5-aminolevulinic acid to induce endogenous porphyrins for the purpose of detection of epithelial cancers is being studied extensively in many centres around the world. The challenge is to prepare an efficacious formulation of 5-ALA for the purpose of cancer detection. In this study, we compared two formulations of topical 5-ALA applications with intravenous administration in NPC/CNE-2 xenografts on balb/c nude mice. One of the formulations was a gantrez muco-adhesive patch and the other was a polyvinyl-pyrolidone muco-adhesive patch. The Karl Storz fluorescence endoscopy system was used to obtain macroscopic fluorescence images. Microscopic fluorescence imaging was done by …

Antioxidation Activity Of Dhea And Its Mechanisms, Sun Yang, Han Rui

Pharmacy Faculty Articles and Research

Objective: The aim of this study was to determine the anti-oxidative activity of a new chemopreventive agent--dehydroepiandrosterone (DHEA), and the mechanisms of action by which DHEA protect the thymocytes and DNA from oxidative damage. Methods: Agarose gel electrophoresis, flow cytometry, single cel! gel electrophoresis, chemiluminescence assay, triazolyl blue tetrazolumbromide (MTT) colorimetry, and three dimensional collagen gel assay were used. Results: In agarose gel electrophoresis, 10 nmol/L DHEA blocked the typical DNA degradation (DNA Ladder) induced by H₂O₂. DHEA 2. 5 nmol/L and 10 nmol/L both significantly decreased the percentage of characteristic apoptotic DNA …

Ouabain Interaction With Cardiac Na+/K+-Atpase Initiates Signal Cascades Independent Of Changes In Intracellular Na+ And Ca2+, Jiang Liu, Jiang Tian, Michael Haas, Joseph I. Shapiro, Amir Askari, Zijian Xie

Pharmaceutical Science and Research

We have shown previously that partial inhibition of the cardiac myocyte Na⁺/K⁺-ATPase activates signal pathways that regulate myocyte growth and growth-related genes and that increases in intracellular Ca²⁺ concentration ([Ca²⁺]i) and reactive oxygen species (ROS) are two essential second messengers within these pathways. The aim of this work was to explore the relation between [Ca²⁺]i and ROS. When myocytes were in a Ca²⁺-free medium, ouabain caused no change in [Ca²⁺]i, but it increased ROS as it did when the cells were in …

Protein Adducts Of Iso[4]Levuglandin E2, A Product Of The Isoprostane Pathway, In Oxidized Low Density Lipoprotein, Robert G. Salomon, Wei Sha, Cynthia Brame, Kamaljit Kaur, Ganesamoorthy Subbanagounder, June O'Neil, Henry F. Hoff, L. Jackson Roberts Ii

Pharmacy Faculty Articles and Research

Levuglandin (LG) E₂, a cytotoxic seco prostanoic acid co-generated with prostaglandins by nonenzymatic rearrangements of the cyclooxygenase-derived endoperoxide, prostaglandin H₂, avidly binds to proteins. That LGE₂-protein adducts can also be generated nonenzymatically is demonstrated by their production during free radical-induced oxidation of low density lipoprotein (LDL). Like oxidized LDL, LGE₂-LDL, but not native LDL, undergoes receptor-mediated uptake and impaired processing by macrophage cells. Since radical-induced lipid oxidation produces isomers of prostaglandins, isoprostanes (isoPs), via endoperoxide intermediates, we postulated previously that a similar family of LG isomers, isoLGs, is cogenerated with isoPs. Now …

Intracellular Reactive Oxygen Species Mediate The Linkage Of Na+/K+-Atpase To Hypertrophy And Its Marker Genes In Cardiac Myocytes, Joseph I. Shapiro, Amir Askari, Zijian Xie, Peter Kometiani, Jie Li, Jiang Liu

Pharmaceutical Science and Research

We showed before that in cardiac myocytes partial inhibition of Na⁺/K⁺-ATPase by nontoxic concentrations of ouabain causes hypertrophy and transcriptional regulations of growth-related marker genes through multiple Ca²⁺-dependent signal pathways many of which involve Ras and p42/44 mitogen-activated protein kinases. The aim of this work was to explore the roles of intracellular reactive oxygen species (ROS) in these ouabain-initiated pathways. Ouabain caused a rapid generation of ROS within the myocytes that was prevented by preexposure of cells to N-acetylcysteine (NAC) or vitamin E. These antioxidants also blocked or attenuated the following actions of …

Synthesis And Evaluation Of Cocaine Analogs For Activity As Cocaine Antagonists And Synthesis Of Novel Prodrugs With Antiarthritic Potential, Bonnie Lisa Barr

MUSC Theses and Dissertations

As a follow up to interest in a new class of agents that have potential for the treatment of arthritic conditions, two series of cocaine derivatives were synthesized. Specifically, an N-alkyl series consisting of the ethyl, n-propyl, isopropyl, n-butyl and benzyl norcocaine derivatives and an N-acyl series consisting of the acetyl, propionyl, butyryl, and benzoyl norcocaine derivatives were synthesized. The structures of these compounds were verified using GC/MS, 1H NMR, and FT-IR with support from elemental analysis. Evaluation of the effect of these cocaine analogs on the inhibition of dopamine uptake represented the biological focus of this project. Each of …

What Is The Risk Of Teratogenicity With The Use Of Selective Serotonin Reuptake Inhibitors During Pregnancy?, Michael Z. Wincor, Mary Gutierrez, Ann Nguyen

Pharmacy Faculty Articles and Research

"The lifetime prevalence of major depressive disorder in women is 10 to 25%, with an average age of onset in the mid-20s.1 Over the nine years that the selective serotonin reuptake inhibitors (SSRis) have been available, for many prescribers, they have become first-line agents in the treatment of depression. In addition, sorne of them are also being used in the treatment of obsessive- compulsive disorder and panic disorder. In light of these facts, itis not unlikely that women of childbearing age would be treated with one of the SSRis. In considering the risks of exposing a fetus to an SSRI, …

Effect Of Ibogaine On Morphine: Induced Modifications Of Palatability, Hardy Joseph Rideout

Theses and Dissertations (Comprehensive)

The ability of the potential anti-addictive agent ibogaine to module the morphine-induced modification of quinine and sucrose palatability was assessed utilizing the taste reactivity test. Ibogaine (40mg/kg) was administered 24 hr prior to an injection of morphine (2 mg/kg), followed 30 min later by a 5 min intraoral infusion of 0.05% quinine solution (Experiment 1) or 10% sucrose solution (Experiment 2). Treatment with morphine enhanced the palatability of both quinine and sucrose solution. Morphine reduced the aversiveness of quinine solution during the 5 min of testing and enhanced ingestive responding to sucrose solution, however, only during min 1 of the …

The Synthesis Of Various Substituted 3-Amino-7-Hydroxy-2,2-Dimethyltetralins And Their Opioid-Related Activities, David Alan Lippman

University of the Pacific Theses and Dissertations

A series of aminotetralones and aminotetralins were synthesized from the common intermediate F, 3-amino-2,2-dimethyl-7-methoxy- 1-tetralone. The final compounds derived from F were simple substituted and/or reduced analogues. The products would allow a progressive structure activity relationship to be drawn based on pharmacological testing.

The common intermediate F was synthesized utilizing a six step procedure starting with p-methoxyphenylacetic acid. The overall yield from the precursor to the F:HC1 was 25%. Compound F was either O-demethylated to form 3-amino-2,2-dimethyl-7-hydroxy-l-tetralone (I) or was dimethylated on the amine and subsequently O-demethylated to yield the 3-dimethylamino-7-hydroxy-2,2-dimethyl-l-tetralone (J). The last major modification was the reduction of …

Synthesis Of Mesoionic Nucleosides As Potential Antineoplastic Agents, Shanaz Mohammedali Tejani

Theses and Dissertations

During the past few decades, analogs of purine nucleosides have been described that are modified either in the heterocyclic base, sugar moiety or both, and many of these modified nucleosides display antiviral and/or antineoplastic activity. The Class II mesoionic purinones are isosteric with their non~mesoionic purinone counterparts. It is conceivable that the mesoionic purinone nucleosides might constitute an entirely novel class of modified nucleosides with potential chemotherapeutic activity. That the mesoionic heterobases are bioisosteric as well as isosteric with non-mesoionic purinones was realized by demonstrating that certain mesoionic xanthine derivatives, such as Anhydro-8-ethylw-5-hydroxy-7-oxo-l,3,4-thiadiazolo[3,2-a]pyrimidinium hydroxide and Anhydro-6-p-chlorobenzyl-8-ethyl-5-hydroxy-7-oxo—l,3,4—thiadiazolo [3,2-a]pyrimidinium hydroxide were comparable …

Meal Interference With Antibiotics Administered Orally In Kentucky Hospitals, Shirley Harper

Masters Theses & Specialist Projects

Hospitals within the State of Kentucky were surveyed to determine if the size of the hospitals influence the frequency of potential meal interference with the administration of oral antibiotics where the "empty stomach" concept must be fulfilled. One hundred and ten hospitals responded to the mailed survey. Of the responding hospitals 103 were short-term and 7 were long-term hospitals. The frequency of conflict was greater for nourishments than with meal interference. Ninety-three and six tenths percent or 103 answered yes when asked if all patients received nourishments on request. The conflicts of potential meal interference ranged from 15 to 40 …

Synthesis And Biological Evaluation Of Sparsomycin Analogues, Scherer Preston Sanders

Theses and Dissertations

In 1962, Owen, Dietz, and Camiener reported the isolation of a new antitumor antibiotic from the culture filtrate of Streptomyces sparsogenes. The structure of the crystalline antibiotic, named sparsomycin, remained elusive until 1970, when Wiley and MacKellar reported results of spectroscopic and degradation studies which elucidated the structure. In addition to the molecular structure, investigators have examined the mechanism of action, toxicity, and related analogues, striving to establish sparsomycin or a synthetic analogue's usefulness as an effective chemotherapeutic agent.

The initial pharmacological evaluation of sparsomycin revealed it possessed activity against KB human epidermoid carcinoma cells, a variety of gram-negative and …

Toxicology And Pharmacology Of N¹-Acetylspermidine And N⁸-Acetylspermidine, Othman A. Alshabanah

University of the Pacific Theses and Dissertations

The polyamines are a group of natural compounds which have been found in almost all living tissues. N¹- and N⁸- acetylspermidine have been known for a considerable time as normal constituents in human urine, but their physiological role is unknown. Recent studies have indicated the presence of enzymes in the tissues capable of converting spermidine into N¹-acetylspermidine and N⁸-acetylspermidine and other enzyme activities which catalyze deacetylation and interconversion reactions.

One approach for determining physiologic activity of an endogenous compound is to observe their pharmacologic and toxicologic effects. In the present study, the …

Synthesis And Evaluation Of Some Arylalkenyl And Arylepoxyalkyl Hydrogen Succinates And Hydrogen Glutarates As Inhibitors Of Rat Liver Β-Hydroxy-Β-Methylglutaryl Coenzyme A Reductase, Paul Emil Marecki

Theses and Dissertations

Atherosclerotic disease is an almost universal phenomenon and increases in severity and frequency with increasing age. Atherosclerosis may contribute to several disorders including bursting of an artery, blockage of an artery, or induction of arterial clotting. The culmination of these diseases is usually premature since at the time of death the unaffected organs are in reasonably satisfactory condition and could have operated for several more years. Among the many factors which act in concert to produce the disease, serum cholesterol levels play a central role. It has been suggested that the lowering of cholesterol levels will provide an effective means …

The Pharmacology Of Rodenticides, S. A. Peoples

Vertebrate Pest Conference Proceedings: 4th (1970)

The compounds used as rodenticides are tremendously varied in their chemical structure and mechanism of action. With a few exceptions, these agents are generally poisonous to all animals, including man, and a great deal of study has been directed to their toxicity in animals other than rodents. However, the development of new compounds as Norbormide and certain antifertility drugs which are highly selective in their action may justify the hope that the ideal rodenticide free of secondary toxic hazards will soon be available. Until this happy announcement is made, a review of the pharmacology of the older compounds is in …

Syntheses And Antimicrobial Activities Of Some 4-Aza-Sitostane Derivatives, Hassan Y. Aboul-Enein

Electronic Theses and Dissertations

Research into the chemical and pharmacological properties of aza­steroids has become of interest because of their potential value as pharmacodynamic and chemotherapeutic agents. A nitrogen atom, for example, would be able to interact, unlike carbon, with a variety of sites in enzymes by means of ionic-ionic, ionic-dipole, dipole-dipole and hydrogen.bonds. Azasteroids having a nitrogen, atom might be adsorbed more strongly or in a different orientation to a given enzyme, and also may produce.a different biologic effect with a new spectrum of biological activities. The pharmacological.activities of a number of synthetic azasteroids, have been reported.

This investigation is concerned with the …