bluuebunny/crossref_metadata_2025_split huggingface dataset:
Renal hemodynamic and excretory effects of n‐0861, a non‐xanthine adenosine A1‐receptor antagonist
Authors: Barrett Richard J. , Wright Kathryn F. , Droppleman David A. 
Published: January 2005

AbstractThe renal hemodynamic and excretory effects of intravenous N‐0861, a non‐xanthine adenosine A1‐receptor antagonist, were evaluated in conscious and anesthetized male Sprague‐Dawely rats. In conscious rats, N‐0861 (10, 30 μmol/kg, iv) significantly increased the excretion of urine, Na+, and K+; UClV was increased only in the rats treated with 10 μmol/kg, N‐0861. The relative excretion of K+ was similar to that of Na+. Lower doses of N‐0861 (1, 3 μmol/kg, iv) had no effect. During clearance studies in anesthetized rats, N‐0861 (3, 10, 30 μmol/kg, iv) had little effect on systemic or renal hemodynamics, but provoked significant saluresis that was poorly related to dose, and that was characterized by a somewhat greater excretion of Na+ and Cl−− relative to K+. These results indicate that the selective adenosine A1 receptor antagonist N‐0861 has little influence on resting renal hemodynamics and suggest that the natriuretic responses are due to inhibition of tubular Na+ reabsorption.
Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S‐312‐d: Therapeutic effects of s‐312‐d on cerebral metabolic impairment in stroke‐prone spontaneously hypertensive rats
Authors: Matsunaga Kazuki , Masui Masao , Ueda Motohiko 
Published: January 2005

AbstractThe therapeutic effects of S‐312‐d on cerebral metabolic impairment were investigated in the stroke‐prone spontaneously hypertensive rats (SHRSP) with apparent stroke symptoms. S‐312‐d was orally administered 10 mg/kg/day (25 μmol/kg/day) to the SHRSP group (SP‐312) for 3 weeks. Several stroke symptoms such as piloerection, hyperreactivity, and limb paralysis in SHRSP were markedly alleviated in SP‐312. Their body weight and food intake also increased. The hypotensive and positive chronotropic effects with S‐312‐d were recovered to pre‐drug levels at 24 h after daily administration. The increases of water, Na+ and Ca2+ and the decreases of K+ and Mg2+ in the cortex of SHRSP administered 1% gum arabic solution (SP‐cont) were significantly improved in SP‐312. The increases of glucose and lactate/pyruvate ratio in the cortex of SP‐cont were also significantly reduced in SP‐312, while the recoveries of the decreased ATP and creatine phosphate in the cortex of SP‐312 were slight. The cholinergic and monoaminergic neurotransmitters in the brain were generally decreased in SP‐cont. The decreased acetylcholine (ACh) and choline acetyltransferase activity (CAT) in the cortex of SP‐cont were significantly restored in SP‐312. In the cortex, the decreased dopamine (DA) in SP‐cont was significantly restored, while the decreased norepinephrine (NE) and 5‐hydroxytryptamine (5‐HT) in SP‐cont were only slightly recovered in SP‐312. However, the decreased NE and 5‐HT in SP‐cont showed marked recovery in the hippocampus of SP‐312. Many biochemical deteriorations in cerebral organs such as marked edema, increases of Na+ and Ca+ contents, and decreases of several neurotransmitters in symptomatic SHRSP, which had some characteristic symptoms of stroke, seemed to be improved by the several pharmacological effects resulting from Ca2+ antagonistic effects of S‐312‐d. These data suggests that S‐312‐d can prevent the deteriorating metabolic changes in SHRSP following the cerebral stroke. © 1994 Wiley‐Liss, Inc.
Versatility of positional scanning synthetic combinatorial libraries for the identification of individual compounds
Authors: Pinilla Clemencia , Appel Jon R. , Blondelle Sylvie E. , Dooley Colette T. , Eichler Jutta , Ostresh John M. , Houghten Richard A. 
Published: January 2005

AbstractPositional scanning synthetic combinatorial libraries (PS‐SCLs) offer a unique and rapid approach for the identification of individual active compounds from libraries made up of millions of compounds for basic research and drug discovery. As presented here, PS‐SCLs are free to interact in solution, and therefore can be screened in virtually any assay system to rapidly identify compounds. For example, a PS‐SCL made up of hexapeptides consists of six separate positional libraries, each composed of mixtures having a single position defined with an amino acid and the remaining positions as mixtures of amino acids. The screening of PS‐SCLs, in most instances, permits the identification of the most active amino acids at each position of a peptide in a single assay. To illustrate the versatility of this combinatorial library approach, three different hexapeptide PS‐SCLs are described: (1) N‐terminal acetylated, (2) N‐terminal non‐acetylated (both composed of L‐amino acids), and (3) N‐terminal acetylated composed of D‐amino acids. Each of the PS‐SCLs is composed of more than 50 million peptides; they are used here to identify: an antigenic determinant recognized by a monoclonal antibody; non‐acetylated peptide sequences that bind to δ opioid receptors; acetylated and non‐acetylated peptide inhibitors of melittin's hemolytic activity; and D‐amino acid peptide inhibitors of trypsin. © 1994 Wiley‐Less, Inc.
Application of one‐bead one‐structure approach to identification of nonpeptidic ligands
Authors: Staňková Magda , Issakova Olga , Sepetov Nikolai F. , Krchňák Viktor , Lam Kit S. , Lebl Michal 
Published: January 2005

AbstractA synthetic chemical library comprised of alkylated and acylated amino acids was synthesized and screened to determine structures that bind to a model target, streptavidin. The library was prepared using “split synthesis” and screened in a solid phase binding assay. The structure of positively reacting compounds was determined using mass spectroscopy. Positive compounds, together with various structural analogs were synthesized and their binding confirmed. Structures containing both an imidazole moiety and a substituted aromatic residue demonstrated binding. © 1994 Wiley‐Less, Inc.
Voltage‐dependent interactions: The influence and significance of membrane potential on drug‐receptor interactions
Authors: Ertel Eric A. , Cohen Charles J. 
Published: January 2005

AbstractSome major drugs exert their therapeutic effect by inhibiting currents through voltage‐gated ion channels. In particular, Na channels are blocked by local anesthetics, Class I antiarrhythmics, and some anticonvulsants (phenytoin and carbamazepine) whereas Ca channels are blocked by dihydropyridines (nifedipine), phenylalkylamines (verapamil), and benzothiazepines (diltiazem). Although their binding site is often present in many different tissues, most of these compounds have a good therapeutic index and are relatively tissue‐specific in their action. Many such drugs have been studied in considerable detail and their mechanisms of action were often found to be similar. In general, drug binding is strongly modulated by the pattern of electrical activity associated with the target channel and is most potent for patterns associated with pathological conditions. The most widely held hypothesis suggests that this happens because nearly all the therapeutically useful blockers of voltage‐gated ion channels have an allosteric interaction with the gating mechanism of the target channel, such that drug binding is greatly favored by specific conformations of the channel. In this review, we describe the different models that have been proposed to account for time‐ and voltage‐dependent block of Na and Ca channels, with particular emphasis on recent advances in our understanding of these phenomena. We also discuss the use of similar principles to describe the action of channel activators and we suggest possible future directions. © 1994 Wiley‐Liss, Inc.
Na+ channels: Structure, function, and classification
Authors: Kirsch Glenn E. 
Published: January 2005

AbstractThe isolation and characterization of cloned Na channels have given new insights into structure‐function relationships. In particular, recent mutational analyses of the tetrodotoxin binding site and the inactivation gate have begun to clarify the structural basis for the phenomena of drug block at the extracellular mouth of the ion‐conducting pore, and regulation of ion conductance by gating at the intracellular mouth. However, much more work remains to be done, particularly in regard to the receptors for the inactivation gate and for the local anesthetic class of drugs. This paper reviews the background, and some of the recent advances and future direction in Na channel structure‐function studies. © 1994 Wiley‐Liss, Inc.
Selective fluorescent ligands for pharmacological receptors
Authors: Baindur Nandkishore , Triggle David J. 
Published: January 2005

AbstractReceptor‐selective fluorescent ligands have come into increasing use as scientific tools for the study of receptor physiology and pathophysiology at the cellular and even the subcellular level. Furthermore, they are being increasingly investigated as tools in drug discovery research. In both cases, techniques employing receptor‐selective fluorescent ligands have proved to be complementary to, and in several cases even superior to, the traditional‐radioligand based techniques. Increasing costs and public concerns associated with radioactive isotope use and dispersal are also making the use of fluoresecent ligands more attractive in research and diagnostic use. With the increasing rate of discovery of new receptors and receptor subtypes and newer more potent and/or selective receptor ligands and drugs, there will be an accompanying need for the design and development of new highly potent and selective fluorescent ligands to aid in the investigation of the physiological and pathophysiological functions of these new receptors and also in the development of drugs acting specifically at these receptors. This review presents a background of development of selected fluorescent ligands, primarily those for small molecule and small peptide based ligands. © 1994 Wiley‐Liss, Inc.
Histamine receptor‐subtype affinities, selectivities, and potencies of emedastine, a novel H1‐selective antagonist, and other ocularly employed antihistamines
Authors: Sharif Najam A. , Xu Shouxi , Yanni John M. 
Published: January 2005

AbstractEmedastine, a novel ocular antihistamine, exhibited nanomolar affinity (Ki = 1.26 nM; pKi = 8.9) for the histamine H1‐receptor and had a markedly lower affinity for histamine H2‐(Ki = 39.8 μM; pKi = 4.4) and H3‐(Ki = 12.6 μM; pKi = 4.9) receptor subtypes. Emedastine was the most H1‐selective antagonist tested, being 31,200 and 10,080 times more active at the H1‐receptor than at H2‐ and H3‐receptors, respectively. In contrast, while other ocularly employed antihistamines like pyrilamine, ketotifen, levocabastine, antazoline, and pheniramine had relatively high affinities for the H1‐receptor, they exhibited significantly lower H1‐selectivities than emedastine. In general, the H1‐receptor affinities of the compounds compared well with their potencies for antagonizing histamine‐induced phosphoinositide (PI) turnover. Emedastine exhibited antagonist potencies (IC50 values) of 1.8, 1.58, and 0.5 nM in human conjunctival epithelial cells, transformed human trabecular meshwork cells, and human corneal fibroblasts, respectively. In conclusion, emedastine is a high affinity and high potency histamine receptor antagonist with a superior H1‐selectivity than other antihistamines tested. Emedastine may therefore be a useful antihistamine for treating symptoms of ocular allergic diseases. © 1994 Wiley‐Liss, Inc.
Sertindole: A limbic selective neuroleptic with potent anxiolytic effects
Authors: Sánchez Connie , Arnt Jørn , Costall Brenda , Domeney Annette M. , Kelly Elisabeth , Naylor Robert J. 
Published: January 2005

AbstractThe anxiolytic potential of the putative neuroleptic sertindole was assessed in various animal models of anxiety in rodents and in the marmoset human threat test. Sertindole facilitates the exploratory behaviour of mice and rats in the black and white two‐compartment box over a large dose range. Sertindole is more potent than diazepam, i.e., minimal effective doses (MED) in the mouse are 0.00023 nmol (0.1 ng/kg) and 0.46 μmol/kg (0.13 mg/kg), respectively, and MED in the rat are 0.23 nmol/kg (0.10 μg/kg) and 35 nmol/kg (10 μg/kg), respectively. Sertindole increases the time that pairs of rats spend in active social interaction (unfamiliar high light conditions) at extremely low doses (MED = 0.000023 nmol/kg [0.01 ng/kg]) being some 19 million‐fold more active than diazepam (MED = 0.44 μmol/kg; 0.13 mg/kg). Sertindole inhibits isolation‐induced aggressive behaviour in the mouse, but only at high doses, and sertindole does not inhibit shock‐induced suppression of drinking or footschock‐induced ultrasonic vocalization in rat. Sertindole similarly shows potent anxiolytic‐like activity in the marmoset human threat test (MED = 23 nmol/kg; 10 μg/kg). The range between anxiolytic doses and sedative doses is very large for sertindole, i.e., sedation is observed at 2,300 nmol/kg (1 mg/kg). © Wiley‐Liss, Inc.
Ganglionic nicotinic acetylcholine receptor activation by the novel agonist ABT‐418
Authors: Briggs Clark A. , Hughes Marion L. , Monteggia Lisa M. , Giordano Tony , Donnelly‐Roberts Diana , Arneric Stephen P. 
Published: January 2005

AbstractABT‐418 was functionally characterized as a neuronal nicotinic acetylcholine receptor (nAChR) channel agonist using preparations that contain nAChRs characteristic of the ganglionic subtypes. In PC12 cells, ABT‐418, like (−)nicotine, activated an inward current that decayed within seconds in the continued presence of agonist. ABT‐418 was 4‐fold less potent than (−)nicotine (EC50 = 214 ± 30 μM and 52 ± 4 μM, respectively) while the efficacy of ABT‐418 was not significantly different from (−)nicotine when the peak response amplitude was measured. Responses to 300 μM ABT‐418 were reversibly inhibited 81 ± 3% by 10 μM mecamylamine, 38 ± 1% by 10 μM dihydro‐β‐erythroidine, and 82 ± 2% by 100 μM dihydro‐β‐erythroidine. These nAChR antagonists affected the response to (−)nicotine similarly. Furthermore, responses to maximal concentrations of ABT‐418 (3 mM) and (−)nicotine (1 mM) were not additive, consistent with ABT‐418 and (−)nicotine acting through the same receptor(s). However, the Hill coefficient for ABT‐418 (1.18 ± 0.20) was smaller than that for (−)nicotine (1.77 ± 0.18), and high concentrations of ABT‐418 appeared to elicit a more rapidly decaying response than did (−)nicotine. In the rat superior cervical sympathetic ganglion also, ABT‐418 was 2.5‐fold less potent than (−)nicotine in blocking nicotinic transmission, presumably through nicotinic receptor desensitization. These studies provide the most direct evidence that ABT‐418 activates nicotinic cholinergic channels, and suggest that ABT‐418 would have reduced potency compared to (−)nicotine in peripheral ganglia, consistent with the reduced side effect liability of this novel nAChR agonist. © Wiley‐Liss, Inc.
Limitations in the use of tubulin polymerization assays as a screen for the identification of new antimitotic agents: The potent marine natural product curacin A as an example
Authors: Hamel Ernest , Blokhin Andrei V. , Nagle Dale G. , Yoo Hye‐Dong , Gerwick William H. 
Published: January 2005

AbstractCuracin A is a newly isolated lipid natural product that binds in the colchicine site of tubulin and inhibits mitosis. We have examined its effects on tubulin polymerization, studied by turbidimetry, under three reaction conditions. In 1.0 M glutamate + 1.0 mM MgCl2, with a 37°C reaction temperature, we could find no concentration of curacin A that completely inhibited polymerization. A maximal inhibitory effect on turbidity development (about 50%) was observed with 5 m̈M drug. Higher drug concentrations induced an abnormal polymerization reaction, which at 40 m̈M differed little from the control reaction except for slightly delayed depolymerization in response to reducing the temperature to 0°C. In 0.8 M glutamate (no MgCl2), with a 30°C reaction temperature, complete inhibition did occur at 3–5 m̈M drug, but higher drug concentrations again induced an abnormal polymerization reaction. With 40 m̈M curacin A this reaction was also similar to the control reaction, except that cold‐induced depolymerization was slightly enhanced relative to the control. When polymerization was induced by microtubule‐associated proteins, maximal inhibition of turbidity development (about 70%) occurred with 2 m̈M drug, with higher curacin A concentrations inducing abnormal polymerization reactions that reached about 60% of the control turbidity readings. Under all three reaction conditions the polymer induced by high concentrations of curacin A consisted of large aggregates of tightly coiled spiral fibers that had a 2–3 filament substructure. The implications of these findings with curacin A are discussed in terms of the use of tubulin polymerization assays as a screen for identifying new antimitotic drugs. © 1995 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
Site‐directed delivery of anthracyclines for treatment of cancer
Authors: Trail Pamela A. , Willner David , Hellström Karl Erik 
Published: January 2005

AbstractThe efficacy of cancer treatment is often limited by the lack of selectivity of anticancer agents for malignant cells. A promising approach for increasing both the efficacy and therapeutic index of anticancer agents is to utilize antibodies, directed against tumor‐associated antigens, to selectively deliver anticancer agents to tumor cells. Antibodies have been used to deliver a variety of anticancer agents including chemotherapeutic drugs, plant and bacterial toxins, and radionuclides. This review concentrates on the chemistry and preclinical biology of immunoconjugates made with members of the anthracycline group of antibiotics. © 1995 Wiley‐Liss, Inc.
Immunotoxins as cancer chemotherapeutic agents
Authors: Siegall Clay B. , Wolff Edith A. , Gawlak Susan L. , Paul Leland , Chace Dana , Mixan Bruce 
Published: January 2005

AbstractImmunotoxins, composed of antibodies linked to protein toxins, are cell‐specific cytotoxic reagents that have been constructed as both chemical conjugates and fusion proteins. A variety of different toxins derived from plants, such as ricin, saporin, and bryodin, and bacteria, including Diphtheria toxin and Pseudomonas exotoxin, have been utilized to construct extremely cytotoxic immunotoxin molecules. Single‐chain immunotoxin fusion proteins composed of cloned antibody variable regions directly fused to toxins have several advantages over chemically conjugated forms, most importantly, enhanced in vivo antitumor activity. BR96 sFv‐PE40 is a single‐chain immunotoxin fusion protein that targets a Lewis‐Y related antigen expressed on the surface of solid tumor cells. Complete regression and, in certain cases, cure of established tumor xenografts have been observed with BR96 sFv‐PE40 administration into rodents. Clinical utility of immunotoxins has shown some promise but has been limited by many factors, most notably vascular leak syndrome (VLS). Our finding that rats serve as a model to study BR96 sFv‐PE40 mediated VLS has led to identification of potential inhibitors of this dose‐limiting toxicity. In summary, immunotoxins, especially single‐chain forms, offer exciting possibilities for therapy of cancer. © 1995 Wiley‐Liss, Inc.
7‐OH‐DPAT, a dopamine D3‐selective receptor agonist, produces contralateral rotation in 6‐hydroxydopamine‐lesioned rats
Authors: McElroy John F. , Ward Kathryn A. 
Published: January 2005

AbstractThe purpose of the present study was to characterize the rotational behavior in unilateral 6‐OHDA‐lesioned rats produced by the high affinity and selective dopamine D3 receptor ligand 7‐OH‐DPAT. Qualitatively similar to the direct‐acting DA agonist apomorphine, 7‐OH‐DPAT causes rats to rotate in a direction contralateral to the side of the nigrostriatal DA pathway lesion. This effect is dose‐dependent and the minimum effective dose is 0.03 mg (0.12 m̈mol)/kg. 7‐OH‐DPAT‐induced rotation is blocked in a dose‐dependent manner by oral pretreatment with the “D2‐like” receptor antagonists haloperidol, eticlopride, or clozapine, but not by the “D1‐like” antagonist SCH 23390. The rank order potency for inhibition of 7‐OH‐DPAT rotation for haloperidol [ID50 = 0.067 mg (0.18 m̈mol)/kg], eticlopride [ID50 = 0.41 mg (1.2 m̈mol)/kg], clozapine [ID50 = 13 mg (40 m̈mol)/kg], and SCH 23390 [ID50 > 90 mg (313 m̈mol)/kg] closely parallels their rank order affinity for binding to either the D2 or the D3 receptor. Pretreatment with the non‐DA receptor antagonists ritanserin (serotonin 5HT2), scopolamine (muscarinic cholinergic), propranolol (betaadrenergic), or naltrexone (opiate), each at relevant pharmacological doses, failed to reduce 7‐OH‐DPAT rotation. Taken together, these results are consistent with mediation of 7‐OH‐DPAT‐induced rotational behavior via an agonist interaction with one or more DA receptors. ©1995 Wiley‐Liss, Inc.
Terlakiren: An orally active renin inhibitor in the guinea pig
Authors: Mangiapane Michael L. , Wester Ronald T. , Holt William F. , Ellery Suzanne S. , Simpson Kelly A. , Schelhorn Teresa M. , Smith Andrew H. , Purcell Irene M. , Murphy William R. 
Published: January 2005

AbstractHuman and monkey renin are very similar, but differ from the renin of species commonly used in screening antihypertensive agents (i.e., dog and rat). This has necessitated the evaluation of renin inhibitors (Rls) in primate models. We have found that many Rls are also active against guinea pig (GP) renin, and thus may be evaluated for mean arterial pressure (MAP) lowering in this species. One such Rl is terlakiren (isopropyl N‐[N‐(4‐morpholinocarbonyl)‐L‐phenylalaninyl‐S‐methyl‐L‐cysteinyl]‐2‐(R)‐hydroxy‐3(S)‐amino‐4‐cyclohexybutanoate, formerly CP‐80,794), an orally active renin inhibitor which lowers MAP and plasma renin activity (PRA) in sodium‐deficient cynomolgus and marmoset monkeys. In vitro, terlakiren's IC50 against primate renin (including man) is ∼ 0.6 and 0.3 nM against GP renin. At iv doses of 0.3–3.0 mg (0.48–4.8 m̈mol)/kg in sodium‐depleted GPs, terlakiren produced 20–30 mmHg falls in MAP which returned to control values in 30–150 min. Oral administration of terlakiren at 30 mg (48.3 m̈mol)/kg reduced MAP 10–15 mmHg and MAP returned to control levels in ∼150 min. Increasing the dose of terlakiren to 50 mg (81 m̈mol)/kg (po) decreased MAP 25–30 mmHg, with a total duration of effect >5 h. Cardiac output and heart rate were unaffected, indicating that the fall in MAP was totally due to decreased total peripheral resistance. Terlakiren had minimal effects on MAP in GPs on a normal sodium diet. The effect of terlakiren on PRA was evaluated in separate studies. Control PRAs for the sodium‐deficient GPs ranged from 15–20 ng Al/ml/h. After 50 mg (81 m̈mol)/kg (po) of terlakiren, there was 81% suppression of PRA (vs. control) at 240 min and 62% suppression at 5 h. Thus, terlakiren was orally active against renin and blood pressure in the sodium‐depleted guinea pig, which appears to be a very good non‐primate alternative for the evaluation of renin inhibitors. ©1995 Wiley‐Liss, Inc.