bluuebunny/crossref_metadata_2025 huggingface dataset:
NPC 205 is a potent and selective adenosine A1, receptor antagonist: Correlation among receptor binding, biochemical, and physiological assays
Authors: Kaplita P. V. , Abreu M. E. , Connor J. R. , Erickson R. H. , Ferkany J. W. , Hicks R. P. , Schenden J. A. , Noronha‐Blob L. , Hanson R. C.
Published: January 2005

The chemical synthesis of 8‐aryl‐1,3‐dialkyl derivatives of xanthine and the ability of these compounds to interact with adenosine A1 and A2 receptors in vitro (in receptor binding, biochemical, and physiological assays) are described. NPC 205 (1,3‐dipropyl‐8‐[4‐hydroxy‐ phenyl]xanthine) was the most potent and A1‐selective antagonist of the series. NPC 205 was twice as potent at PACPX (1,3‐dipropyl‐8‐[2‐amino‐4‐chlorophenyl]xanthine) and at least 20‐fold more potent than 8‐phenyltheophylline to inhibit specific binding of [3H]‐cy‐clohexyladenosine to guinea pig and rat brain membranes. Along with NPC 189 (1,3‐dimethyl‐8‐[4‐hydroxyphenyl]xanthine), NPC 200 (1,3‐dipropyl‐8‐phenylxanthine), and PACPX, NPC 205 also was a more potent antagonist of A1‐receptor‐mediated inhibition of adenylate cyclase (AC) in rat cortex than A2 receptor‐coupled stimulation of AC in PC‐12 cell membranes. NPC 205 was, in fact, 30‐fold more potent and fourfold more selective than PACPX for the AC‐coupled A1 receptor function and exhibited competitive interactions with A1 receptors. In isolated guinea pig atria, NPC 205, NPC 189, NPC 200, and PACPX all reversed 5′N‐ethyl‐carboxamidoadenosine (NECA)‐induced depression of tension and rate. In the Langendorff isolated perfused guinea pig heart preparation, NPC 205 was more potent than PACPX in reversing NECA‐mediated depression in developed tension and rate (A1‐mediated) and, unlike PACPX, had no effect on coronary perfusion pressure (A2‐mediated). Neither NPC 205 or PACPX had significant competitive inhibitory effects on rat heart phosphodiesterase III activity in vitro. Together, the results suggest that NPC 205 is a highly potent, selective, and competitive antagonist of adenosine A1 receptors and should be useful for examining the physiological significance of A1 receptors in vitro and in vivo.
Effect of repeated administration of clonidine on adrenergic, cholinergic (muscarinic), dopaminergic, and serotonergic receptors in brain regions of rats
Authors: Gulati Anil , Hussain Ghazala , Srimal Rikhab Chand
Published: January 2005

Clonidine (0.1 mg/kg) or its vehicle was administered orally to rats for 2 months. A significant decrease in mean blood pressure was observed in clonidine treated rats. Chronic administration of clonidine in rats produced alterations in central receptors. In hypothalamus and medulla, clonidine in treatment increased the Bmax value of 3H‐dihydroergocryptine binding to α‐adrenergic receptors. In cortex, clonidine treatment increased the Bmax value of 3H‐spiroperidol binding to dopaminergic receptors. Clonidine treatment produced a decrease in the Bmax value in cortex while in hypothalamus and medulla, an increase in the Bmax value of 3H‐quinuclydinyl benzylate (QNB) binding to muscarinic receptors was observed. In medulla, clonidine treatment increased the Bmax value of 3H‐5‐hydroxytryptamine (HT) binding to 5‐HT1 receptors. No change was observed in dissociation constant (Kd) values of any 3H‐ligand in any brain region. In vitro studies showed interaction of clonidine with 3H‐dihydroergocryptine and 3H‐QNB. It can be concluded from the present study that chronic administration of clonidine produces an up‐regulation of α‐adrenergic, cholinergic (muscarinic), and serotonergic (5‐HT1) receptors in brain regions mainly involved in cardiovascular regulation.
Hepatoprotective activity of picroliv, the active principle of Picrorhiza kurrooa, on rat hepatocytes against paracetamol toxicity
Authors: Visen P. K. S. , Shukla Binduja , Patnaik G. K. , Kaul Surabhi , Kapoor N. K. , Dhawan B. N.
Published: January 2005

Picroliv, the active principle an iridoid glycoside mixture isolated from the plant Picrorhiza kurrooa, showed dose‐dependent (0.75–12 mg/kg × 7 days) protective activity on isolated hepatocytes (ex vivo) against paracetamol‐induced hepatic damage in rats. It increased the percent viability of the hepatocytes. Picroliv also restored the normal values of enzyme (glutamic oxaloacetic transaminase [GOT], glutamic‐pyruvic transaminase [GPT], and alkaline phosphatase) both in the isolated hepatocyte suspension as well as in the serum. Picroliv was found to be more potent than silymarin, a known hepatoprotective agent.
The effect of denbufylline (BRL 30892) on cortical pO2, pH, and microflow in a rat model of focal cerebral ischaemia
Authors: Angersbach Dieter
Published: January 2005

The effects of denbufylline (DBF), a novel xanthine derivate, have been investigated in a rat model of focal cerebral oligaemia. In this model a small (15–20 mm2) oligaemic area was produced by occlusion of pial arteries with a diameter of ca. 100 μm. The oligaemic area was characterized by a marked fall in cortical microflow, pO2, and pH, this being indicative of severe impairment of tissue nutrition leading to tissue acidosis. It is considered that the situation in this model may be analogous to that occurring in multi‐infarct dementia (MID) patients. DBF improved cerebral blood flow, enhanced cortical tissue oxygenation, and led to normalization of extracellular pH in the rat model of focal cerebral ischaemia. The results suggest that denbufylline ameliorates microcirculation and metabolism in brain areas affected by infarcts of small arteries.
CK‐2289 and milrinone in dogs with propranolol‐induced heart failure: Effect of ouabain
Authors: Greenberg Stanley S. , Touhey Beatrix , Hom Gary
Published: January 2005

We examined the interaction between ouabain and CK‐2289, a new bivalent inodilator, and compared their effect with that of milrinone on the hemodynamic and myocardial energetic parameters of anesthetized dogs with propranolol‐induced heart failure (PIHF). Mongrel dogs (13–19 kg) of either sex were anesthetized with pentobarbital sodium (35 mg/kg, i. v.) and instrumented for routine hemodynamic measurements using an open‐chest, artificially ventilated preparation. PIHF was produced by decreasing left ventricular (LV) dP/dTmax by 50% from control values with an initial infusion of 0.5 mg/kg of propranolol followed by continuous infusion of 0.02 to 0.08 mg/kg of propranolol to maintain PIHF. This was followed by infusion of saline (2 ml, i. v., n = 12/group) or ouabain (25 μg/kg, i. v., n = 12/group).

Thirty min later saline and ouabain‐treated animals (4/group) were given 2 doses of saline (1 and 2 ml, i. v.), CK‐2289 (0.01 and 0.03 mg/kg, i. v.) or milrinone (0.03 and 0.1 mg/kg, i. v.) 30 min apart. Hemodynamic parameters were monitored continuously. Myocardial oxygen consumption (MVO2) was monitored 15 and 30 min after each dose of drug. CK‐2289 increased LV dP/dTmax and LV dP/dTmin by 60 and 120% and 42 and 43%, respectively. Mean arterial pressure decreased by 12% after the high dose of CK‐2289. CK‐2289 did not affect heart rate, while LV end diastolic pressure decreased by 5 mmHg. CK‐2289 increased LV work and did not affect or decrease LV contractile efficiency. Ouabain enhanced the myocardial energetic profile of CK‐2289 by allowing CK‐2289 to stimulate more work at a lower MVO2, thereby increasing myocardial efficiency. Milrinone had a profile similar to CK‐2289 but in ouabain‐pretreated animals with PIHF milrinone stimulated less work at the same MVO2, thus decreasing contractile efficiency. Thus, ouabain may enhance the myocardial energetic effects of CK‐2289.
Blood pressure effects of monoamine oxidase inhibitors in response to orally administered tyramine in the rat
Authors: Carroll Mary , Beek Otto
Published: January 2005

The reversible monoamine oxidase‐A inhibitors BW 1370U87, BW 616U76, brofaromine, and moclobemide, and the irreversible nonselective monoamine oxidase inhibitor phenelzine were compared for potentiation of the pressor response to oral tyramine. Conscious rats were pretreated with doses of the monoamine oxidase inhibitors sufficient to produce 80% inhibition of brain monoamine oxidase, and then were challenged with orally administered tyramine. Blood pressure was monitored prior to and after tyramine, and peak pressor responses were compared. At a dose of 15 mg/kg tyramine, the pressor response of BW 1370U87 was statistically similar to the vehicle control response. BW 616U76, brofaromine, and moclobemide elicited mild tyramine pressor effects, whereas phenelzine resulted in a marked elevation of blood pressure. Higher doses of tyramine elicited blood pressure elevations from all of the monoamine oxidase inhibitors.
Mitogen‐inducible prostaglandin G/H synthase: A new target for nonsteroidal antiinflammatory drugs
Authors: Xie Weilin , Robertson Donald L. , Simmons Daniel L.
Published: January 2005

Prostaglandins have been shown to be involved in many different biological processes, under both normal and pathological conditions. As the key enzyme in the production of prostaglandins and thromboxanes, prostaglandin GIH synthase (PGHS) has been well characterized, including extensive studies as a pharmacological target of the nonsteroidal antiinflammatory drugs (NSAIDs). The gene for this enzyme has been cloned, sequenced, and characterized from sheep, mouse, and human sources. Recently, a new form of this enzyme, a mitogen‐inducible PGHS (miPGHS), was identified. Comparisons between these two genes and their protein products have identified significant differences, including structural differences in the proteins and their mRNAs. The genes encoding these two isoenzymes are not coordinately regulated in cultured cells or in tissues. The discovery of this second form of PGHS may change our understanding of how NSAlDs exert their effects. miPGHS is believed to be a new, unique target of NSAIDs which could have a different sensitivity to many of these drugs, compared to the previously identified PGHS. © 1992 Wiley‐Liss, Inc.
A computerized system for measuring cell length of single isolated smooth muscle cells
Authors: Moummi Chafiq , Woodford Mark
Published: January 2005

We have developed a state‐of‐the‐art computerized system to measure the cell length (contraction/relaxation) of single isolated gastrointestinal smooth muscle cells in response to different drugs. The system is composed of a microscope to which a video camera is attached and a video monitor which is connected to the video camera output. The image on the TV screen is analyzed by a digital image processor. The data acquisition and initial analysis are done directly on a personal computer. The acquired data are sent immediately via a network to a database on a minicomputer. From this database, comprehensive data reports and graphs can be generated and hard copy obtained. The system was validated by testing the contractile activity of endothelin‐1 and the relaxant effect of isoproterenol on single smooth muscle cells isolated from the rat colon. This system offers a valuable pharmacological tool for drug screening to the pharmaceutical industry. © 1992 Wiley‐Liss, Inc.
Long‐term use of appetite suppressant medication: Rationale and recommendations
Authors: Stallone Daryth D. , Stunkard Albert J.
Published: January 2005

We propose a change in the use of “appetite suppressant” medication in the treatment of obesity: use it on a long‐term basis or not at all. This proposal is based on the theory that “appetite suppressant” medication acts primarily by lowering the regulated level of body weight. We review the concept of the regulation of body weight and present evidence that body weight is regulated in animals of normal weight and in some obese animals. We show that the concept of the regulation of body weight also applies to variations of body weight produced by endogenous factors, such as those related to hibernation, as well as by experimental interventions, such as brain lesions and “appetite suppressant” medication. Evidence of body weight regulation in normal weight and obese humans is presented and clinical significance discussed. We conclude with a discussion of a new role for “appetite suppressant” medication in the treatment of obesity. © 1992 Wiley‐Liss, Inc.
SCH 39166, a novel dopamine D1 receptor antagonist: In vitro investigation of its glucuronidation and potential species differences
Authors: Tedford Clark E. , Ruperto Vilma B. , Coffin Vicki L. , Cohen Mary , Libonati Michele , Barnett Allen
Published: January 2005

SCH 39166 is a novel benzonaphthazepine that is a selective dopamine D1 receptor antagonist. It is currently undergoing clinical trials in humans for possible use as an antipsychotic medication. To date, no studies have been presented describing the metabolism of SCH 39166. Therefore, the present studies investigated the possible in vitro glucuronidation of SCH 39166 from both rodent and squirrel monkey liver microsomes. Comparisons were made with the classic D1 antagonist, SCH 23390, a benzazepine which undergoes extensive glucuron dation in the rat. Additionally, dose response and duration of action of SCH 39166 on the conditioned avoidance paradigm (CAR) in both rats and squirrel monkeys were compared to the dose response and duration of action of SCH 23390 in these species. Results demonstrated that 3H‐SCH 39166 was glucuronidated by both rat and monkey liver microsomes. In studies with rat liver microsomes, the rate of glucuronidation of SCH 39166 and the affinity for the glucuronosyltransferase enzyme were equivalent to those of SCH 23390. In vivo behavioral studies also indicated no differences in either the dose‐response curves or the time course of behavioral effects for either D1 antagonist after oral administration in the rat. In contrast, the rate of glucuronidation in squirrel monkey liver microsomes of SCH 23390 was 3–4 times faster than that of SCH 39166. Moreover, these findings consistent with in vivo behavioral studies in squirrel monkeys, in which the duration of action of SCH 23390 was much shorter than SCH 39166. © 1992 wiley‐Liss, Inc.
Comparative pharmacology of dothiepin, its metabolites, and other antidepressant drugs
Authors: Heal David , Cheetham Sharon , Martin Keith , Browning John , Luscombe Graham , Buckett Roger
Published: January 2005

The pharmacology of dothiepin and its human metabolites, northiaden, dothiepin sulfoxide, and northiaden sulfoxide, has been studied to determine whether the latter contribute to the therapeutic or side effects profile of the parent tricyclic antidepressant. In vitro, dothiepin was a potent noradrenaline and 5‐hydroxytryptamine (5‐HT) uptake inhibitor, while its secondary amine metabolite, northiaden, was selective for noradrenaline. However, the sulfoxide metabolites were almost inactive as uptake inhibitors. Dothiepin and northiaden prevented the ptosis produced by tetrabenazine in mice and reserpine in rats and increased the mobility of mice in the Porsolt test. After repeated administration, both drugs decreased β‐adrenoceptor number and stimulation of the receptor‐linked adenylate cyclase by noradrenaline. Dothiepin had a higher affinity than northiaden for histamine H1, muscarinic and various adrenergic and 5‐HT receptors in vitro, whereas the sulfoxide metabolites were inactive. Overall, the data indicate northiaden almost certainly contributes to the therapeutic actions of dothiepin, but the sulfoxide metabolites do not. However, the latter are also unlikely to produce any side effects. A comparison of dothiepin with other tricyclics revealed important divergences in the profiles of uptake inhibition and receptor affinity. Thus, dothiepin is generally similar to imipramine in its pharmacology, but it differs considerably from amitriptyline and doxepin. © 1992 Wiley‐Liss, Inc.
Microgram doses of chlordiazepoxide and diazepam do not increase punished responding in the rat
Authors: Pollard Gerald T. , Howard James L.
Published: January 2005

Microgram doses of chlordiazepoxide and diazepam injected intraperitoneally (i.p.) have been reported to change rodent behavior, notably in two observational procedures that predict anxiolysis. We tested half‐log doses from 0.03 to 10 mg/kg in the Geller‐Seifter conflict preparation in the rat. Only doses in the milligram range showed any tendency to increase punished responding. The results do not support the hypothesis that microgram doses might be anxiolytic. © 1992 Wiley‐Liss, Inc.
Purinoceptor nomenclature: A status report
Authors: Abbracchio Maria P. , Cattabeni Flaminio , Fredholm Bertil B. , Williams Michael
Published: January 2005

In the field of purinoceptors, the P1‐adenosine and P2‐ATP system proposed by Burnstock some 15 years ago has provided a cornerstone for receptor nomenclature [Burnstock and Kennedy, 1985: Gen Pharmacol 16:433–440.] For the adenosine/P1 receptor class, the generally accepted nomenclature has been that of A1 and A2, while P2 receptor have been defined as P2x, P2y, and so on. The incorporation of newer receptors, characterised either by the actions of available compounds on defined tissues systems or by the cloning and expression of purinoceptors, into this framework provides the challenge of melding the “old” with the “new”. An open meeting of the IUPHAR Purine Receptor Nomenclature Subcommittee held at the Purine Club's “Purine '92” in Milan in June of 1992 focused on this issue with input from world leaders in the area of purine research. It was recommended from this meeting that adenosine receptors, in addition to the classical A1, A2a, and A2b receptors, be further described by numerical subscript, i.e., A3, A4, until such time as pharmacological and molecular biological data provided evidence for their relationship, if any, to the A1/A2, classes. For ATP and other purine nucleotide receptors, subtypes of which were designated by letters rather than numbers, the P2X and P2Y, receptors proposed by Burnstock major families of P2 receptors utilizing ligand‐gated cation channels and G‐proteins, respectively. Some concerns were expressed in regard to the apparent random walk through the alphabet in of the IUPHAR nomenclature initiative. © 1993 Wiley‐Liss, Inc.
Neuromodulatory roles of purines
Authors: Fredholm Bertil B. , Johansson Björn , van der Ploeg Ingeborg , Hu Ping Sheng , Jin Shaoyu
Published: January 2005

In the present overview we focus on two aspects: (a) the role of adenosine as an endogenous cerebroprotective agent and (b) the possible significance of adenosine‐dopamine interactions. Adenosine is a normal constituent of the brain extracellular environment. Its levels greatly increase upon neuronal excitation or as a consequence of decreased supply of metabolic substrates. Via its receptors it tends to limit its own formation in several ways. By increasing blood flow and glucose uptake it increases substrate supply. By decreasing the release of excitatory neurotransmitters and by causing hyperpolarization it decreases energy demand. This suggests a role as an endogenous cerebroprotective agent, something which is supported by several lines of pharmacological evidence.

The adenosine A2a receptor is enriched in dopamine rich‐areas of the brain and it has been found to be colocalized with dopamine D2 receptors on medium‐sized spiny neurons in the striatum. Recent evidence shows that A2 agonists decrease agonist binding to dopamine D2 receptors. Furthermore, adenosine receptor antagonists have been shown to produce behavioural effects that are due to enhanced dopaminergic neurotransmission. It is suggested that the A2‐ D2‐receptor interactions may explain some of the stimulatory effects of low doses of caffeine. © 1993 Wiley‐Liss, Inc.
Differential effects of early chronic lead exposure on postnatal rat brain NMDA, PCP, and adenosine A1 receptors: An autoradiographic study
Authors: Brooks William J. , Petit Ted L. , Leboutillier Janelle C. , Nobrega Jose N. , Jarvis Michael F.
Published: January 2005

The deleterious effects of postnatal lead (Pb) exposure on neural development, synaptic plasticity, and cognitive function have been well documented in laboratory animals. While the exact mechanisms by which Pb produces long‐lasting neurotoxicity remain unknown, recent evidence suggests that Pb may interact with and/or disrupt the N‐methyl‐D‐aspartate/phencyclidine receptor complex and the associated ion channel. In addition to perturbations of excitatory amino acid neurotransmission, chronic Pb exposure may also have deleterious effects on inhibitory mechanisms such as that provided by purinergic neuromodulation. In order to further examine the possibility that alterations of both excitatory and inhibitory neurotransmission may contribute to the neurotoxic actions of Pb, the effects of early Pb exposure on ligand binding to postnatal rat brain N‐methyl‐D‐aspartate (NMDA), phencyclidine (PCP), and adenosine A1 receptors were examined using quantitative autoradiography techniques. Rat pups nursed mothers exposed to 4% PbCO3 in their diet or a Na2CO3 control diet from postnatal day 1 (P1) to P25. At P25, rats were sacrificed and the regional distributions of brain NMDA, PCP, and adenosine A1 receptors were examined. Chronic lead exposure was found to produce a specific increase in [3H]CGP 39653 binding to NMDA receptors in the hippocampus. [3H]1‐(1‐[2‐thienyl)cyclohexyl]‐piperdine ([3H]TCP) binding to PCP receptors was largely unaffected by the chronic Pb treatment. In contrast, [3H]cyclohexyladenosine ([3H]CHA) binding to adenosine A1 receptors was markedly reduced in many brain regions with the largest decreases observed in the cerebellum. These results indicate that neonatal Pb exposure produces a specific alteration of both excitatory and inhibitory neuromodulatory mechanisms in the postnatal rat forebrain that may underlie the behavioral hyperactivity and increased seizure sensitivity associated with Pb neurotoxicity. © 1993 Wiley‐Liss, Inc.
Role of serotonin in ethanol abuse
Authors: Wallis Cleatus J. , Rezazadeh S. Mehdi , Lal Harbans
Published: January 2005

Several subclasses of serotonin receptors (5‐HT1a, 5‐HT1b, 5‐HT1c, 5‐HT2, and 5‐HT3) have been implicated in the control of ethanol (EtOH) related behaviors, such as: (1) voluntary EtOH consumption, (2) anxiety occurring during EtOH withdrawal (EW), (3) interoceptive stimuli produced by EtOH, and (4) modulation of EtOH intoxication. Serotonin modulation of neuronal excitability and modulation of hormone release may be important mechanisms contributing to the development and/or maintenance of ethanol tolerance/dependence by modulating emotional behavior (anxiety), homeostasis, and adaptive processes. This review examines our current understanding of serotonin's contribution to ethanol abuse. © 1993 wiley‐Liss, Inc.
Interaction of berbamine and chloroquine or artemisinin against chloroquine‐sensitive and ‐resistant plasmodium falciparum in vitro
Authors: Ye Zuguang , Van Dyke Knox , Yang Baizhen
Published: January 2005

Antimalarial activity of berbamine (BB), alone or in combination with chloroquine (CQ) or artemisinin (qinghaosu, QHS), was studied using CQ‐sensitive and ‐resistant strains of Plasmodium falciparum in vitro. BB was found to have antimalarial effects with IC50 values of 603 and 359 nM, respectively, for the drug‐sensitive and ‐resistant strains of P. falciparum, indicating that BB exhibited some selective antimalarial activity against the drug‐resistant parasite. Its antimalarial efficacy and selectivity appeared to be less than that of tetrandrine (TT), however, when BB was combined with CQ, an antagonistic interaction was found against the CQ‐sensitive parasite, while a potentiating antimalarial action was observed with the CQ‐resistant parasite. When BB was tested in combination with QHS, a complex interaction was found—one was additive for the CQ‐sensitive parasite and the other was potentiating for the CQ‐resistant parasite. The above data suggested that the BB combination with either CQ or QHS is a promising candidate for an antimalarial remedy to treat at least CQ‐resistant falciparum parasites which cause malaria. © 1993 wiley‐Liss, Inc.
Promise of nicotinic‐based therapeutic treatments
Authors: Levin Edward D. , Rosecrans John A.
Published: January 2005

Nicotine has a wide variety of pharmacological effects. Some of these, such as improved attentiveness and memory, quickened reaction time, reduced appetite, and lessening of stress can be viewed as beneficial and may partially underlie tobacco use. They also suggest therapeutic uses of nicotine. Like any drug, nicotine has adverse effects as well, such as convulsant actions and cardiovascular effects. Also, like a variety of therapeutic drugs from caffeine to codeine, nicotine has the adverse potential to become habit forming or addictive. Many of the health damaging effects of tobacco use, such as cancer and lung disease, seem to result from compounds present in tar. Eliminating the more than 4,000 different compounds present in tar goes a long way in reducing adverse effects associated with nicotine intake. When developing nicotine for therapeutic use, it is critical to determine the mechanisms of its actions so that its beneficial effects can be maximized and its adverse effects can be minimized. This might be achieved with alternate routes of delivery of nicotine such as the skin patch or with novel nicotinic ligands currently under development. © 1994 Wiley‐Liss, Inc.
Effects of nicotinic agonists and antagonists on spatial working memory in normal adult and aged rats
Authors: Widzowski Daniel V. , Cregan Edward , Bialobok Paul
Published: January 2005

The present study had two goals (1) to examine the effects of treatments with nicotinic agonist (nicotine) and antagonist (mecamylamine) on working memory in normal adult rats (14 months of age), and (2) to determine if treating aged (36 to 42 months of age), memory‐impaired rats with nicotine could improve their memory function. Memory testing was carried out using a delayed non‐matching to position paradigm in a T‐maze. Rats were trained to run down one arm of the maze (e.g., right) on an information run and then, after a variable memory delay period of 10, 90, or 180 sec, run down the other arm (e.g., left). In normal adult rats after water injection, memory accuracy was inversely related to memory delay (> 90, 75, and 67% accuracy at the 10, 90, and 180 sec delays, respectively). Administration of nicotine (0.1 or 0.4 mg/kg), or mecamylamine (2.5 or 5 mg/kg), or combinations of these drugs had no significant effects on memory in these rats. However, mecamylamine alone or in combination with nicotine reduced running speed in the T‐maze in normal adults, indicating that the drugs did produce some behavioral effects. In aged rats, memory accuracy after water injection was much lower than that of younger adults, averaging 64, 57, and 50% at 10, 90, and 180 sec delays. Interestingly, nicotine injections of 0.1 or 0.4 mg/kg resulted in highly significantly improved accuracy in the memory task. The deficit in memory accuracy in aged rats, evident even at the shortest delay period (10 sec), suggests that the rats may have had impairments in attention or visual discriminatory ability. If this is so, then the beneficial effects of nicotine observed in this study may be more related to its effects on attention rather than memory directly. © 1994 Wiley‐Liss, Inc.
Effect of sertindole on raised mesolimbic dopaminergic activity in the rat
Authors: Domeney Annette M. , Arnt Jörn , Costall Brenda , Naylor Robert J. , Sánchez Connie , Smith Annie G.
Published: January 2005

The effect of sertindole in models of mesolimbic dopamine excess in the rat was evaluated. Sertindole (0.0057–0.011 μmol/kg = 2.5–5 μg/kg, sc) and haloperidol (0.13–0.27 μmol/kg = 50–100 μg/kg, ip) inhibited the hyperactivity caused by the acute intra‐accumbens injection of amphetamine (20 μg). The administration of sertindole (0.0057–2.8 μmol/kg = 2.5 μg–1.25 mg/kg, sc daily), haloperidol (0.027–0.40 μmol/kg = 10–150 μg/kg, ip bd) or clozapine (15–31 μmol/kg = 5–10 mg/kg, ip, bd) during a 13‐day period of dopamine infusion (25 μg/24 h) into the nucleus accumbens reduced the dopamine‐induced hyperactivity response to control levels, except at the highest dose which reduced activity to below control levels. Locomotor activity remained at control levels after discontinuing the dopamine/sertindole treatment regimen, whereas discontinuation of the dopamine/haloperidol treatment regimen resulted in rebound hyperactivity. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc) given either once daily or once every 2 days prevented the development of hyperactivity in the intra‐accumbens dopamine infusion model. One injection given every 4 days failed to modify the response to a dopamine infusion. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc daily) inhibited hyperactivity caused by unilateral infusion of dopamine (50 μg/24 h, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test). In contrast to haloperidol, sertindole failed to initiate circling behaviour following unilateral, intrastriatal injection. In conclusion, sertindole, like haloperidol and clozapine, can reduce raised mesolimbic dopaminergic activity in the rat. Sertindole differs from haloperidol by its ability to return the hyperactivity response to control levels. © 1994 Wiley‐Liss, Inc.
Chronic toxicity study with the serotonin antagonist amesergide administered nasogastrically to rhesus monkeys for one year
Authors: Seyler David E. , Murphy‐Farmer Candice M.
Published: January 2005

The chronic toxicity of amesergide, a selective (5HT2/5HT1c) serotonin antagonist, was evaluated in rhesus monkeys given daily nasogastric doses of 0, 5, 10, or 22.5 mg/kg for 1 year. An initial high dose of 25 mg/kg was reduced after approximately 1 week of dosing due to severe behavioral effects, including lethargy, a trance‐like appearance, and rigidity, that interfered with the animal's ability to eat and drink. The behavioral effects, although still present at the new high dose of 22.5 mg/kg were less intense and subsided prior to subsequent daily dosing. All animals survived the treatment period. Clinical signs associated primarily with early treatment at the 25‐mg/kg dose level resulted in reductions of body weights and food consumption. After the high dose was reduced from 25 mg/kg to 22.5 mg/kg, there were no significant effects on body weight gain or food consumption when compared to controls. Plasma concentrations of amesergide and its metabolites increased in a dose‐dependent fashion. Areas under the plasma concentration‐time curve (AUC) and peak plasma concentrations (Cmax) decreased substantially as the study progressed. Stress‐related decreases occurred in leukocytic and erythrocytic parameters of high‐dose males, but values returned to near pretest by study termination. Organ weights as well as gross and histological examination of tissues from animals of all treatment groups revealed no treatment‐related lesions. No adverse effects occurred at daily doses of 5 or 10 mg/kg. © 1994 Wiley‐Liss, Inc.
Amylin and Syndrome‐X
Authors: Young Andrew A. , Rink Timothy J. , Vine William , Gedulin Bronislava
Published: January 2005

A 37 amino‐acid peptide, amylin, is secreted from the pancreatic β‐cell in response to stimuli similar to those causing insulin secretion. Plasma amylin levels are generally elevated under circumstances where insulin is elevated, including in insulin resistance and in essential (obesity‐related) hypertension. Several of amylin's actions may contribute to key features of insulin resistance and the insulin resistance syndrome (Syndrome‐X). Actions on muscle glycogen metabolism, Cori cycle activity, and endogenous glucose production may contribute to glucose intolerance while amylin's effects to suppress β‐cell secretion could account for the secretory defect observed in early glucose intolerance. Amylin also potently increases plasma renin activity, and could contribute to the hypertension that is associated with obesity and insulin resistance.
Anxiolytic properties of (+) s 20499, a novel serotonin 5‐HT1A full agonist, in the elevated plus‐maze and social interaction tests
Authors: Curle Peter F. , Mocaer Elisabeth , Renard Pierre , Guardiola Béatrice
Published: January 2005

Previous studies have shown that (±) S 20244 (8‐(4‐[N‐(5‐methoxychroman‐3‐yl)N‐propylamino] butyl) 8‐azaspiro[4,5]decane‐7,9 dione) and its isomers (+) S 20499 and (−) S 20500 are full agonists at 5‐HT1A receptors. In the present study, the effects of these three compounds were investigated in two animal models of anxiety, the elevated plus‐maze and social interaction tests. Subcutaneous administration of (±) S 20244 (19 μmol/kg−1.9 μmol/kg), (+) S 20499 (470 μmol/kg) or (−) S 20500 (94–940 μmol/kg) or per os administration of (+) S 20499 (190 μmol/kg−19 μmol/kg) produced anxiolytic‐like effects in the elevated plus‐maze while per os administration of (−) S 20500 was without effect. Subcutaneous administration of (±) S 20244 (19 μmol/kg−1.9 μmol/kg) or per os administration of (+) S 20499 (190 μmol/kg−19 μmol/kg) also produced anxiolytic‐like effects in the social interaction test. With both substances, bell‐shaped dose‐response relationships were found. The absence of activity of (−) S 20500 when administered per os suggests that the distribution and/or absorption kinetics of the two isomers may be different. In conclusion, (±) S 20244 and (+) S 20499 both display anxiolytic‐like activity in the elevated plus‐maze and social interaction tests.
Recent advances in the generation of chemical diversity libraries
Authors: Desai Manoj C. , Zuckermann Ronald N. , Moos Walter H.
Published: January 2005

In recent years, screening in combination with a diverse compound collection has become a powerful method for discovering leads for the ever‐increasing number of new biologically active peptides, proteins, receptors, and enzymes discovered continually. As a result, the rapid generation and screening of compound libraries (collections) have recently become important major tools in the search for novel lead structures. Diverse collections of compounds have been acquired by many strategies; these include (1) natural products from plants, fermentation, marine organisms, insect toxins, and ethnic pharmacotherapies; (2) recombinant randomized peptide libraries (often referred to as biological diversity); (3) multiple peptide synthesis; and (4) non‐peptidic synthetic libraries. The present review provides an overview of the recent advances in the field of peptide and non‐peptidic synthetic libraries. The progress made thus far is broadly divided into two categories: (1) Amide based libraries. These libraries share the concepts of the peptide library strategies; much of the referenced work thus refers to peptides, reflecting the bias of the literature to date. (2) Non‐amide based libraries. This promising technology combines solid phase synthesis with classical organic synthesis to provide large numbers of compounds with desirable bioavailability and pharmacokinetics for screening. The basic premise behind the second approach is that the high affinity ligands, when identified, will be much more likely to become useful therapeutic agents than the compounds discovered from amide based libraries. Synthesizing small heterocyclic ring systems that use ligands of diverse biological activity via combinatorial strategies is a fast developing branch of medicinal chemistry. We are at an early state in the development of combinatorial chemistry. However, this dramatic convergence of technologies represents a fundamental advance in medicinal chemistry and promises to play a major role in future drug discovery efforts. © 1994 Wiley‐Less, Inc.
Membrane pathways for drug/ion channel interactions: Molecular basis for pharmacokinetic properties
Authors: Herbette Leo G.
Published: January 2005

This review focuses on the interactions of certain classes of drugs that are known to bind to membrane‐bound ion channel/receptors. The concepts described here have broad applications to various ion channels as well as membrane bound receptors that are not ion channels such as the superfamily of G protein coupled receptors. Since data spanning from the molecular to the clinical field currently exists for drugs that bind to the voltage gated calcium channel, this review will highlight this rather narrow scope. It is to be appreciated that the concepts, as described, may have applicability to other membrane‐bound receptors. The focus will be on the calcium channel antagonist drugs of the 1,4 dihydropyridine type that bind to the L type calcium channel. Clearly an evolution in their molecular design has been brought to a point where these molecules are not only amphiphilic but increasingly lipophilic. Simply stated, this means that these drugs can readily transport across cell membranes accessing both hydrophilic and hydrophobic environments, although they have also become more soluble in the membrane bilayer. From an equilibrium point of view these molecules prefer to reside in the lipid bilayer hydrocarbon core; from a kinetic point of view they spend more time, on average, solvated within membranes than outside membranes, but their rates of entry into and exit from membranes do not appear to be related solely to their intramembranal equilibrium concentration. This biophysical understanding appears not only to define the molecular pathways for drug binding to the calcium channel receptor, but also to explain differences in the overall clinical pharmacokinetics observed for different drugs in this class. The potency of calcium antagonists is primarily related to their binding affinity to the calcium channel with a variable degree of dependency on the solvation of the drug in the membrane. The pharmacokinetic profile of calcium antagonists, although influenced to some degree by interactions with the target receptor, appears to be largely dictated by their interactions with the cell membranes at the molecular level. These interactions are distinctly different for each calcium antagonist but they can be classified into a few subgroups to explain drug onset and duration of action. © 1994 Wiley‐Liss, Inc.
Biochemical and biophysical studies of the interaction of class I antiarrhythmic drugs with the cardiac sodium channel
Authors: Zamponi Gerald W. , Duff Henry J. , French Robert J. , Sheldon Robert S.
Published: January 2005

Class I antiarrhythmic drugs block the cardiac sodium channel and are now used widely for a variety of cardiac arrhythmias. The nature of the interaction of the drugs with these channels, and their mechanism of action, have been areas of considerable recent interest. Here we review several aspects of drug action. Evidence that sodium channel blockade itself is antiarrhythmic arises from experiments in which the sodium channel‐specific toxin tetrodotoxin was shown to prevent ventricular fibrillation in rabbit hearts. A radioligand binding assay for the cardiac sodium channel was then developed using [3H]Batrachotoxinin (BTX) Benzoate and freshly isolated rat cardiac myocytes. Class I antiarrhythmic drug binding identified in this model fits conventional criteria for binding to a receptor. This receptor behaves like an allosteric protein; class I antiarrhythmic drugs appear to bind to and stabilize closed channels. The mechanism of drug binding and electrophysiologic consequences have been examined in a number of model systems by microelectrode studies, whole cell voltage clamping, and more recently voltage clamp studies of single isolated channels in lipid bilayers. Using the latter method, we have shown that lidocaine causes two distinct kinds of sodium channel blockade. The first is a very slow block which can be demonstrated with simple aryl compounds. The second kind of block is a very rapid block which can also be caused by simple alkyl amines. Thus, the two major structural moieties of lidocaine each cause a specific form of block. The structure‐activity relationships of class I drugs were explored with homologs of lidocaine in the radioligand binding assay. With this method the existence of a number of receptor subdomains has been demonstrated, each of which recognizes specific structural moieties of class I drugs. Finally, we have explored both drug proarrhythmia and drug resistance. Drug proarrhythmia may be due to homogeneous slowing of conduction with little effect on refractoriness. One form of drug resistance may be due to induction of synthesis of new cardiac sodium channels by exposure to animals with chronic class I drug administration. Mexiletine induces a three‐fold increase in rat cardiac sodium channels within 3 days due to increased sodium channel mRNA synthesis. Thus drug resistance might be due to drug‐induced increases in the numbers of cardiac sodium channels. © 1994 Wiley‐Liss, Inc.
In vivo pharmacological profile of 9‐hydroxyrisperidone, the major metabolite of the novel antipsychotic risperidone
Authors: Megens Anton A. H. P. , Awouters Frans H. L.
Published: January 2005

9‐Hydroxyrisperidone (9OH‐risperidone) is the major metabolite of the new antipsychotic risperidone. 9OH‐risperidone was compared with risperidone in a series of pharmacological tests in rats; ritanserin and haloperidol were included as reference compounds in tests for 5HT2 and D2 antagonism, respectively. 9OH‐risperidone closely resembled risperidone and showed similar effects at closely related doses (respective subcutaneous [sc] ED50s in mg/kg in parentheses): 5HT2 antagonism: reversal of tryptamine cyanosis (0.00059/0.0011), inhibition and blockade of tryptamine seizures (0.032/0.014 and 0.11/0.056), inhibition of tryptamine tremors (0.34/0.049), inhibition and blockade of mescaline head twitches (0.056/0.037 and 0.098/0.049); D2 antagonism: inhibition and blockade of apomorphine behavior (0.34/0.22 and 4.1/1.2), inhibition and blockade of amphetamine agitation (0.15/0.056 and 0.51/0.59) and oxygen consumption (0.049/0.016 and 0.17/0.64), behavioral disinhibition (0.069/0.31) and depression (4.6/4.7) in amphetaminized rats; histamine H1 antagonism: protection from compound 48/80 lethality (0.018/0.014); α1‐adrenoceptor antagonism: protection from norepinephrine lethality (0.17/0.074); α2‐adrenoceptor antagonism: reversal of clonidine's antidiarrheal effect (0.29/0.67), reversal of xylazine loss of righting (16/2.4); and behavioral effects: slight and pronounced catalepsy (2.0/0.59 and 3.6/3.0), slight and pronounced palpebral ptosis (0.30/0.19 and 2.0/0.89), muscular hypotonia (4.7/3.6), hypothermia (4.1/2.0), inhibition of acetic acid writhing (1.2/0.34), and depression of motor activity (0.13/0.062 for vertical, 0.49/0.18 for horizontal, and 5.0/2.8 for total movements). Up to 10 mg/kg, both compounds were devoid of anti‐muscarinic and anti‐nicotinic activity, failed to affect the lethal effects of KCN, nitrogen, BaCl2 and ouabain, and did not block castor oil diarrhea. The acute oral LD50 values of the compounds were comparable. Both 9OH‐risperidone and risperidone differed markedly from haloperidol as indicated by: (1) predominant central 5HT2 antagonism (comparable to that of ritanserin); (2) high doses of catalepsy; (3) gradual depression of motor activity; (4) pronounced behavioral disinhibitory effects in amphetaminized rats; (5) inhibition of amphetamineinduced oxygen consumption preceding inhibition of amphetamine agitation. As metabolic conversion of risperidone to 9OH‐risperidone does apparently not result in any marked change in activity profile, its major consequence seems to be a prolongation of duration of action. © 1994 Wiley‐Liss, Inc.
Administration of a hemoglobin solution decreases hypoxia and increases radiation response in a rat mammary carcinoma
Authors: Teicher Beverly A. , Dupuis Norman P. , Liu Fang , Robinson Michael F. , Menon Krishna
Published: January 2005

Administration of an ultrapurified bovine hemoglobin solution (8 ml/kg, iv) to female Fisher 344 rats bearing the 13672 mammary carcinoma implanted subcutaneously in the hind leg reduced the hypoxic fraction of the tumor from 49 to 36% with normal air breathing and to 28% with carbogen (95% oxygen/5% carbon dioxide) breathing. When administration of the hemoglobin solution was followed by single dose (10, 20, or 30 Gray) local radiation therapy, the dose modifying factor was 1.5 with air breathing and 2.7 with carbogen breathing. For fractionated radiation therapy, 2, 3, or 4 Gray was delivered locally daily for 5 days. When the hemoglobin solution was administered prior to each radiation fraction and air breathing maintained, there was a 1.8‐fold increase in tumor growth delay. When daily hemoglobin solution administration was accompanied by carbogen breathing, there was a 2.6‐fold increase in tumor growth delay. Less frquent administration of the hemoglobin solution (alternate days, twice weekly or once weekly) resulted in 1.5‐ to 1.7‐fold increases in tumor growth delay. The greatest increases in tumor oxygenation occurred shortly after administration of the hemoglobin solution; in fact at 12 h post administration of the hemoglobin solution, the tumors appeared to be more hypoxic than prior to administration of the hemoglobin solution. By 24 h post administration of the hemoglobin solution, the oxygen tension profile of the tumors were returning to pretreatment levels. Further investigation of this ultrapurified hemoglobin solution in cancer is warranted. © 1995 Wiley‐Liss, Inc.
Comparison of the proteolytic susceptibilities of homologous L‐amino acid, D‐amino acid, and N‐substituted glycine peptide and peptoid oligomers
Authors: Miller Susan M. , Simon Reyna J. , Ng Simon , Zuckermann Ronald N. , Kerr Janice M. , Moos Walter H.
Published: January 2005

A series of homologous L‐amino acid, D‐amino acid, and both parallel and anti‐parallel (retro) sequence N‐substituted glycine peptide and peptoid oligomers were prepared and incubated with a series of enzymes representative of the major classes of proteases. Each respective L‐amino acid containing peptide sequence was readily cleaved by the appropriate enzyme, namely Ac‐L‐ala‐L‐leu‐L‐phe‐L‐ala‐L‐leu‐L‐arg‐NH2 by chymotrypsin, Ac‐L‐ala‐L‐ala‐L‐ala‐L‐leu‐L‐phe‐L‐arg‐NH2 by elastase, Ac‐L‐ala‐L‐phe‐L‐glu‐L‐leu‐L‐ala‐L‐ala‐NH2 by papain, Z‐L‐ala‐L‐his‐L‐phe‐L‐phe‐L‐arg‐L‐leu‐NH2 by pepsin, Ac‐L‐phe‐L‐ala‐L‐arg‐L‐ala‐L‐arg‐L‐asp‐NH2 by trypsin, and Ac‐L‐ala‐L‐tyr‐Lala‐L‐phe‐OH for carboxypeptidase A. In contrast, equivalent D‐amino acid containing and N‐substituted glycine containing oligomers were cleaved minimally or not at all by the respective enzymes. The N‐substituted glycine peptoids represent a new class of combinatorial diversity for lead discovery with improved pharmaceutical characteristics relative to L‐amino acid containing peptides. © 1995 Wiley‐Liss, Inc.
Status of safety pharmacology in the pharmaceutical industry—1995
Authors: Sullivan Andrew T. , Kinter Lewis B.
Published: January 2005

Safety pharmacology contributes to the pharmacological characterization, risk assessment, and registration of new drugs; however, safety pharmacology strategies and study designs for new drugs vary widely across the pharmaceutical industry. We surveyed 26 pharmaceutical companies for how and why they conduct safety pharmacology studies. All conduct/contract safety pharmacology studies; 19 have safety pharmacology units, seven do not; ten locate responsibility for safety pharmacology in development, 16 in discovery (or research). Total staff range from two to 16 full‐time equivalents (fte)/unit. Most companies conduct evaluations of cardiovascular and CNS functions, less evaluate respiratory, gastrointestinal and renal functions; a few conduct a ligand‐binding/activity panel as part of their pharmacological profiling. Resources to complete a company's standard safety pharmacology program are ∼1–4 fte/compound. One‐third of companies use a maximum tolerated dose (MTD) for safety pharmacology studies, two‐thirds use multiples of pharmacological or therapeutic doses. Approximately half conduct safety pharmacology studies to Good Laboratory Practices (GLPs) and use the 1992 Japanese guidelines only as a guide or outline. Company clinicians are most often cited as the “primary customer” for whom Safety Pharmacology studies are done, followed by research and development scientists, and then regulatory authorities. The results suggest that most companies conduct safety pharmacology for its contribution to risk assessment and critical care management. © 1995 Wiley‐Liss, Inc.