bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure‐activity studies of N,N‐dialkyl and cycloalkyl carbamate esters of dimethylethanolamine and choline with nicotinic and muscarinic cholinergic properties
Authors: Saraswati Manda , Lerner‐Marmarosh Nicole , Wang David X. , Sheu Shey‐Shing , Sharma Viranda , Abood Leo G. 
Published: January 2005

AbstractStructure‐activity studies were performed on a series of newly synthesized N‐sub‐stituted carbamate esters of choline and dimethylethanolamine which exhibited either or both nicotinic and muscarinic cholinergic properties. Substitutions on the carbamyl N consisted of varying lengths of dialkyls, diphenyl, and various heterocycles. The compounds were evaluated for their nicotinic and muscarinic receptor binding properties in rat brain membranes, their effect on muscarinic receptor‐activated phosphoinositide (PI) turnover in rat cortical slices, and for muscarinic receptor‐mediated intracelluar Ca release in a mouse adrenal carcinoma cell line transfected with an m1 muscarinic cholinergic receptor gene. N,N‐diethylcarbamylcholine had the highest affinity for nicotinic cholinergic receptors; the Ki value of 1 × 10−9 M approached that of nicotine and being 1/5 that for the dimethyl analogue. With increasing chain length of the dialkyl substituents the nicotinic affinity progressively decreased, while muscarinic affinity increased. N,N‐diphenylcarbamylcholine had a Ki value of 1 × 10−7 M for nicotinic receptors and exhibited nicotinic antagonist activity. Contrary to the results with [3H]‐N‐methylcarbamylcholine binding, the tertiary derivatives exhibited higher Ki values for [3H]‐3‐quinuclidinyl benzilate binding than the quarternaries; the tertiary dibutyl and diphenyl had the highest affinities with Ki values of 4 × 10−7 M. The inhibition of muscarinic receptor‐mediated PI turnover and release of intracellular calcium were related to the muscarinic antagonist potency of the compounds. © 1994 Wiley‐Liss, Inc.
Antidiabetic and antiobesity effects of a highly selective β3‐adrenoceptor agonist (CL 316,243)
Authors: Largis Elwood E. , Burns Michael G. , Muenkel Helen A. , Dolan Jo Alene , Claus Thomas H. 
Published: January 2005

AbstractA third β‐adrenoceptor subtype has been cloned form the rat, mouse, and human genomes. The presence of these receptors primarily on adipose tissue has raised the possibility that β3‐adrenoceptor selective agonists may be useful antiobesity agents. CL 316,243 is a highly selective β3‐agonist; it has a <30,000 to 1 β3‐to‐β1‐adrenoceptor selectivity ratio and a 10,000 to 1 β3‐to‐β2‐adrenoceptor selectivity ratio in in vitro functional assays. In vivo, animals were treated with CL 314,698, a diester prodrug of CL 316,243, which is rapidly converted to CL 316,243. In obese (ob/ob) and diabetic (db/db) mice, treatment with CL 314,698 reduced their hyperglycemia to the euglycemia of their lean littermates, and decreased plasma insulin levels. In obese mice, the compound also caused decreased weight gain despite increased food consumption, and the decreased weight was due to loss of fat while lean body mass was spared. CL 314,698 treatment also improved both glucose and insulin tolerance in obese mice, suggesting that it decreased insulin resistance. CL 314,698 also prevented further weight gain, without affecting food consumption, in rats previously made obese by feeding a high fat diet. The compound reduced plasma insulin and triglyceride levels, and reduced fat pad weights, while having no effect on plasma glucose, cholesterol, thyroxine, or T3 levels or on skeletal muscle weight. Decreased weight gain without decreased food consumption suggested that CL 316,243 stimulated thermogenesis. Treatment of obese mice for 3 weeks with CL 316,243 increased thermogenesis by 45% as measured by indirect calorimetry. Thus, CL 316,243 is a potent, β3‐adrenoceptor selective agonist with thermogenic, antidiabetic, and antiobesity properties in several models of non‐insulin dependent diabetes and obesity.
Developmental aspects of the Adipose tissue renin‐angiotensin system: Therapeutic implications
Authors: Crandall David L. , Herzlinger Helen E. , Saunders Brian D. , Kral John G. 
Published: January 2005

AbstractAdipose tissue possesses considerable growth potential, and excess adipose tissue mass is associated with noninsulin dependent diabetes mellitus (NIDDM). Adipose tissue is a significant source of angiotensinogen, the precursor of angiotensin II (All), a vasoactive peptide with in vitro mitogenic effects. The renin‐angiotensin system remains only partially identified in adipose tissue, however, and knowledge of whether All has a physiologic role in this tissue is dependent in part upon other components of the system being characterized. We have chosen to further investigate aspects of the renin‐angiotensin system in separate adipose tissue depots of rats during growth and development of the tissue. Either epididymal or retroperitoneal adipose tissue was examined in young lean, or adult obese male Sprague‐Dawley rats. Adipose tissue was subjected to collagenase digestion, yielding separate vascular and fat cell fractions. Each fraction was analyzed for angiotensin converting enzyme (ACE) activity and All receptor binding capacity. ACE activity was significantly greater when expressed per gram of adipose tissue in the young lean rats. Vascular and fat cell fractions exhibited All receptors of high affinity, with a greater density of receptors observed in the epididymal adipose tissue fractions. Incubation of adipocytes with exogenous All was associated with the release of prostaglandin into the medium, and analyses of adipocyte cytosol indicated the presence of angiotensinogen. Growing rats given oral losartan, an All receptor antagonist, once daily (15 mg/kg) for 2 weeks exhibited reductions in body weight gain, fat mass, fat cell volume, and All receptor number. These data further document the presence of a peripheral renin‐angiotensin system in anatomically distinct adipose tissue depots at different stages of growth. While the characterization of the effects of All upon adipose tissue development remains incomplete, future investigations with agents affecting the adipocyte renin‐angiotensin system could provide additional information on the role of this system in adipose tissue growth.
Effect of glycosides of Streblus asper on motility, glucose uptake, and certain enzymes of carbohydrate metabolism of Setaria cervi
Authors: Singh Som N. , Chatterjee Ranjit K. , Srivastava Arvind K. 
Published: January 2005

AbstractThe in vitro effects of two pure glycosides, i.e., asperoside (K029) and strebloside (K030) isolated from a traditionally used medicinal plant Streblus asper on the bovine filarial parasite Setaria cervi females were studied. Both K029 and K030 caused death of the worms within 2 to 3 hours at concentrations of 10 μg/ml (1.7 pmoles) and were found to inhibit motility and glucose uptake of the parasites at lower concentrations (0.1 μg/ml; 0.17 pmoles). These glycosides also inhibited the incorporation of [U‐14]C‐glucose into macromolecules of S. cervi females. Parasites preincubated with either K029 or K030 had lowered profiles of glucokinase (EC 2.7.1.2), malate dehydrogenase (EC 1.1.1.37) and succinate dehydrogenase (EC 1.3.99.1) activities, suggesting that the lethal effects of the glycosides were due to effects on glucose metabolism.
Interrelationship of general pharmacology studies with drug discovery and development, clinical medicine, and regulatory affairs
Authors: Fossa Anthony A. , Allan Buchholz R. 
Published: January 2005

AbstractGeneral Pharmacology/Safety Pharmacology studies are being used increasingly to support registration of clinical drug candidates. The value of these studies and the possible impact on the drug discovery and development processes is being recognized as evidenced by the increasing number of companies implementing formal General Pharmacology/Safety Pharmacology groups. The interactions of other departments such as Discovery, Drug Metabolism, Toxicology, Clinical Medicine, and Regulatory Affairs with General Pharmacology are highly dependent on the positioning within the particular organization and the goals set for General Pharmacology studies. The nature of these interactions and how they can be used to the advantage of drug discovery and development programs are discussed.
General pharmacology, the international regulatory environment, and harmonization of guidelines
Authors: Lumley Cynthia E. 
Published: January 2005

AbstractThe performance of general pharmacology procedures on new drug candidates supports both drug discovery and safety assessment activities; however, the potential contribution of general pharmacology to safety assessment has had less attention than other aspects of non‐clinical testing. Pharmaceutical companies are divided as to whether or not general pharmacology is integrated with the rest of toxicology testing or carried out as part of the discovery program, and, recently, discussions have taken place within Europe as to whether or not these studies should be subject to Good Laboratory Practice (GLP) conditions. All three regions (the United States, Europe, and Japan) require data on the pharmacological properties of new drugs to be included in a marketing application. This should cover primary and secondary pharmacological effects, and should provide information concerning potential adverse reactions. In addition, Europe and the United States request non‐clinical data on potential drug interactions. However, the most detailed requirements are described in the Japanese guidelines. This paper reviews the current regulatory environment in the European Community (EC), Japan, and the United States, highlighting some general features of the three regulatory systems which are relevant to general pharmacology, and summarising the specific guidelines for these studies in the three regions. Although there are significant differences between the detailed Japanese general pharmacology requirements and the more flexible Western approach, it is not clear that it is appropriate to include general pharmacology within the international harmonization discussions. Rather, deregulation in this area is a desirable goal for the future.
In vitro screens and functional assays to assess receptor pharmacology
Authors: Sills Matthew A. 
Published: January 2005

AbstractIn the drug discovery process, compounds that demonstrate therapeutic potential must be free of undesirable side effects in order to reach the clinic. Compounds that interact with more than one target, such as a receptor, have the potential to elicit side effects, in comparison to those compounds that are selective for a single target. One predictive measure of whether a compound demonstrates specificity is to profile a compound's activity through a series of receptor binding assays in what is termed a safety screen. If a compound demonstrates activity, further studies are subsequently performed in functional assays in order to determine whether the compound possesses agonist or antagonist activity at that receptor. This article discusses some of the basic tenets of receptor pharmacology and their application to safety assessment.
Thrombolytic activity of YM866, a novel modified tissue‐type plasminogen activator, in a rabbit model of jugular vein thrombosis
Authors: Kawasaki Tomihisa , Kaku Seiji , Sakai Yumiko , Takenaka Toichi 
Published: January 2005

AbstractThe thrombolytic activity of a novel modified t‐PA analog, YM866, was compared with that of recombinant t‐PA (t‐PA) in rabbits with experimental jugular vein thrombosis. Thrombus was induced in an isolated segment of the jugular vein from a mixture of whole autologous blood and thrombin. Thirty minutes after the induction of thrombus, YM866 was administered by iv bolus injection, while t‐PA was given by the same method or by a 60‐min iv infusion. Thrombi were removed 70 min after iv bolus injection or 10 min after the termination of iv infusion, and thrombus size was measured by total protein content in the isolated thrombus. Both YM866 and t‐PA exhibited dose‐dependent thrombolysis; the thrombolytic activity of YM866, however, was 4 times greater than that of t‐PA. The improved thrombolytic activity of YM866 correlated with its relatively higher antigen levels in plasma, which result from its prolonged biological half‐life. Depletion of plasma fibrinogen to less than 20% of baseline levels was observed in all groups. Template bleeding time was not significantly altered in any group. These results suggest that YM866 offers the potential for clinical use in thrombolytic therapy by iv bolus injection for patients with venous thromboembolic diseases. © 1994 Wiley‐Liss, Inc.
Sub‐library composition of peptide libraries: Potential application in screening
Authors: Furka ÁrpáD 
Published: January 2005

AbstractPeptide sub‐libraries and omission sub‐libraries derived from parent peptide libraries synthesized with the portioning‐mixing method are defined. They can be distinguished by their order, i.e., the number of non‐varied positions or omission positions in the molecules. The number of types of sub‐libraries as well as the number of their components depend on both the order and the number of residues. Sub‐libraries belonging to a given residue number and a given order altogether form a kit. The paper outlines the potential use of sub‐libraries and other kinds of partial libraries in identification of the bioactive components of peptide and other kinds of biooligomer libraries. © 1994 Wiley‐Less, Inc.
Dopamine uptake inhibitory activity of novel tryptamine 5‐HT1 receptor ligands
Authors: Lebel Lorraine A. , Nowakowski Jolanta T. , Macor John E. , Fox Carol B. , Kenneth Koe B. 
Published: January 2005

AbstractIn the search for novel serotonin receptor ligands, a series of 5‐thiazolyl‐N,N‐dimethyltryptamine derivatives was synthesized which exhibited high affinity binding to 5‐HT1A, 5‐HT1B, and 5‐HT1D receptors and the functional characteristics of receptor agonists. One member, 5‐(4‐anilnomethyl‐2‐thiazolyl)‐N,N‐dimethyltryptamine (CP‐110,330), was found also to be a potent and selective inhibitor of dopamine uptake in rat striatal synaptosomes. This activity was confirmed by its potent displacement of [3H]N(1‐[2‐benzo(b)thiophenyl]cyclohexyl piperidine (BTCP) binding to the dopamine transporter in striatal membranes. A limited structure‐activity study indicated that optimal dopamine uptake blocking activity was obtained when the thiazole C4 substituent consisted of phenyl with a 2‐atom spacer. The potent effect of these 5‐HT1 receptor ligands on dopamine uptake can be rationalized by the observation that the flexibility of these tryptamine molecules allows the superimposition of the phenyl ring and amino group of the side chain with the corresponding moieties of tametraline, a known catecholamine uptake inhibitor of fixed conformation. A related compound, 3‐(R‐N‐methyl‐2‐pyrrolidinylmethyl)‐5‐(4‐benzyl‐2‐thiazolylamino)‐1H‐indole (CP‐146,662) showed similar potent binding affinity to 5‐HT1 receptors and the dopamine transporter. Compounds with this dual serotonergic and dopaminergic activity may have utility as antidepressant agents. As potent dopamine uptake inhibitors, they may also have application in the treatment of cocaine addiction. © 1994 Wiley‐Liss, Inc.
Inhibition of gastric mucosal damage by santonin pretreatment in rats
Authors: Al‐Harbi Mohammed M. , Qureshi Shoeb , Ahmed Mohammad M. , Raza Muhammad , Miana Ghulam A. , Afzal Mohammad , Shah Arif H. 
Published: January 2005

AbstractThe effect of santonin pretreatment on gastric mucosal injuries caused by 80% ethanol, 25% NaCl, 0.2 M NaOH, indomethacin, and combined treatment of ethanol and indomethacin was investigated in rats. The effects caused by ethanol on gastric mucus secretion, gastric levels of non‐protein sulfhydryl groups, and malondialdehyde and histopathological effects were also investigated. Santonin pretreatment at oral doses of 30, 60, and 120 mg/kg (121.8, 243.6, and 487.2 μmol/kg) provided a dose‐dependent protection against the ulcerogenic effects of different necrotising agents used. Further pretreatment with santonin afforded a dose‐dependent inhibition of ethanol‐induced depletion of stomach wall mucus, proteins, nucleic acids, non‐protein sulfhydryl groups, and an increase in malondialdehyde levels in gastric tissue. The histopathological lesions induced by ethanol in the gastric mucosa were also protected by santonin pretreatment. The protective effect of santonin against alcohol damage to the gastric‐wall mucosa may be mediated through its effects on mucus production, nucleic acids, and non‐protein sulfhydryl generation and its free‐radical scavenging. © Wiley‐Liss, Inc.
Ras farnesylation as a target for novel antitumor agents: Potent and selective farnesyl diphosphate analog inhibitors of farnesyltransferase
Authors: Manne Veeraswamy , Ricca Carolyn S. , Brown Johnni Gullo , Tuomari Anne V. , Yan Ning , Patel Dinesh , Schmidt Robert , Lynch Mark J. , Ciosek Carl P. , Carboni Joan M. , Robinson Simon , Gordon Eric M. , Barbacid Mariano , Seizinger Bernd R. , Biller Scott A. 
Published: January 2005

AbstractProtein prenylation is increasingly recognized as an important mechanism by which functional association of proteins to membranes is mediated. Ras proteins, regulators of cell proliferation and differentiation, are among the proteins that undergo farnesylation, one of the two prenylation modifications known. Since ras proteins are activated into hyperactive oncogenic versions in a wide variety of human cancers, agents that down modulate ras activity could be antineoplastic. Therefore, inhibitors of farnesyltransferase have the potential to be of therapeutic value as anticancer agents due to their ability to block ras processing and hence its function. We describe the identification of two farnesyl pyrophosphate (FPP) analogs that are potent and selective inhibitors of farnesyltransferase. While showing no toxicity to untransformed cells, a pivaloyloxymethyl ester of one of these inhibitors blocked ras mediated transformation of NIH 3T3 cells. In addition, both the ester and its parent acid inhibited ras farnesylation as measured by incorporation of labeled mevalonate into ras proteins in whole cells. Thus, this is the first report of an FPP analog to show biological activity by inhibiting ras processing in whole cells. © 1995 Wiley‐Liss, Inc.
Diagnosing the decline of major pharmaceutical research laboratories: A prescription for drug companies
Authors: Weisbach Jerry A. , Moos Walter H. 
Published: January 2005

AbstractDespite dramatically increasing expenditures for in‐house pharmaceutical research and development (R&D) at major drug companies, few internally discovered, breakthrough products are on the horizon. In contrast, and for significantly less private funding, biotechnology companies are playing an ever more significant role in generating promising biomedical product candidates. For a variety of factors, ranging from financial and management to scientific in nature, we suggest that the twentieth century has encompassed the rise and decline of major pharmaceutical discovery research laboratories. Herein, we provide a concise background to the industry and its current predicament. Having diagnosed some of the problems inherent to the existing organizations, we provide a prescription for change, which places pharmaceutical companies at the center of constellations of alliances with biotech ventures. We posit that, for the same or even fewer dollars, pharmaceutical companies could significantly enhance existing research productivity, with less risk, and with potentially higher rewards. Where this approach to be adopted broadly and successfully, the effect on patients, the healthcare industry, numerous major corporations, their employees and stockholders, and the economy in general, could be “just what the doctor ordered”! These lessons and proposals may also have merit in other research‐based industries. © 1995 Wiley‐Liss, Inc.
General pharmacology of SDZ WAG 994, a potent selective and orally active adenosine A1 receptor agonist
Authors: Wagner Heribert , Milavec‐Krizman Maria , Gadient Fulvio , Menninger Klaus , Schoeffter Philippe , Tapparelli Carlo , Pfannkuche Hans‐Jürgen , Fozard John R. 
Published: January 2005

AbstractThe pharmacological properties of 6‐cyclohexyl‐2′‐0‐methyladenosine (SDZ WAG 994)—a potent, selective, and orally active adenosine A1 receptor agonist—are described. SDZ WAG 994 is a potent (KD 23 ± 2 nM, n = 5) and selective (1,090‐fold vs. A2A receptors) displacer of binding to pig striatal A1 receptors and behaves as a full agonist at the A1 receptors coupled negatively to adenylate cyclase in rat adipocytes (pEC50 6.4 ± 0.2, n = 3), those which induce contraction of rat spleen (pEC50 7.1 ± 0.1, n = 13) and those which suppress the response to autonomic nerve stimulation in guinea‐pig ileum (pIC50 6.6 ± 0.1, n = 4) and rat kidney (pIC50 6.0 ± 0.1, n = 6). The compound has negligible affinity (pEC50 < 4, n = 5) for the A2B receptor which mediates relaxation of guinea‐pig aorta. In spontaneously hypertensive (SH) rats SDZ WAG 994, 0.05–0.5 mg/kg (0.14–1.4 μmol/kg) po, caused dose‐related and sustained (> 5 h) falls in blood pressure (BP) and heart rate (HR) and suppressed plasma renin activity (PRA); the cardiovascular effects could be immediately and fully reversed by an intravenous injection of 8‐(p‐sulphophenyl)theophylline, 20 mg/kg (56.4 μmol/kg). SDZ WAG 994 given via the food at 0.4 and 1.2 mg/kg/day (1.1 and 3.3 μmol/kg/day) for 7 or 14 days, respectively, induced dose‐related hypotension and bradycardia which were well maintained throughout the treatment periods. In the conscious, normotensive dog, SDZ WAG 994, 1 and 3 mg/kg (2.8 and 8.3 μmol/kg) po, induced substantial, sustained falls in BP which were accompanied by tachycardia. In salt depleted squirrel monkeys, SDZ WAG 994, 0.1–0.3 mg/kg (0.28–0.83 m̈mol/kg) iv or 0.2–0.6 mg/kg (0.56–1.7 μmol/kg) po caused dose‐related and sustained (> 5 h) bradycardia and suppression of PRA but no change in BP. In rhesus monkeys, SDZ WAG 994, 0.1–1.2 mg/kg (0.28–3.3 μmol/kg) po induced sustained bradycardia and suppression of PRA and the plasma free fatty acid and triglyceride concentrations. The data establish SDZ WAG 994 as a potent, selective, and orally active adenosine A1 receptor agonist with therapeutic potential in certain cardiovascular and/or metabolic disease states. © 1995 Wiley‐Liss, Inc.