bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenibut (β‐Phenyl‐GABA): A Tranquilizer and Nootropic Drug
Authors: Lapin Izyaslav 
Published: August 2010

ABSTRACTPhenibut (β‐phenyl‐γ‐aminobutyric acid HCl) is a neuropsychotropic drug that was discovered and introduced into clinical practice in Russia in the 1960s. It has anxiolytic and nootropic (cognition enhancing) effects. It acts as a GABA‐mimetic, primarily at GABABand, to some extent, at GABAAreceptors. It also stimulates dopamine receptors and antagonizes β‐phenethylamine (PEA), a putative endogenous anxiogenic. The psychopharmacological activity of phenibut is similar to that of baclofen, ap‐Cl‐derivative of phenibut. This article reviews the structure‐activity relationship of phenibut and its derivatives. Emphasis is placed on the importance of the position of the phenyl ring, the role of the carboxyl group, and the activity of optical isomers. Comparison of phenibut with piracetam and diazepam reveals similarities and differences in their pharmacological and clinical effects. Phenibut is widely used in Russia to relieve tension, anxiety, and fear, to improve sleep in psychosomatic or neurotic patients; as well as a pre‐ or post‐operative medication. It is also used in the therapy of disorders characterized by asthenia and depression, as well as in post‐traumatic stress, stuttering and vestibular disorders.
S 17092: A Prolyl Endopeptidase Inhibitor as a Potential Therapeutic Drug for Memory Impairment. Preclinical and Clinical Studies
Authors: Morain Philippe , Lestage Pierre , De Nanteuil Guillaume , Jochemsen Roeline , Robin Jean‐Loïc , Guez David , Boyer Pierre‐Alain 
Published: August 2010

ABSTRACTAny treatment that could positively modulate central neuropeptides levels would provide a promising therapeutic approach to the treatment of cognitive deficits associated with aging and/or neurodegenerative diseases. Therefore, based on the activity in rodents, S 17092 (2S,3aS,7aS)‐1 ([(R.R)‐2‐phenylcyclopropyl]carbonyl)‐2‐[(thiazolidin‐3‐yl)car‐bonyl]octahydro‐1H‐indole) has been selected as a potent inhibitor of cerebral prolyl‐endopeptidase (PEP). By retarding the degradation of neuroactive peptides, S 17092 was successfully used in a variety of memory tasks. These tasks explored short‐term, long‐term, reference and working memory in aged mice, as well as in rodents and monkeys with chemically induced amnesia or spontaneous memory deficits. S 17092 has also been safely administered to humans, and showed a clear peripheral expression of its mechanism of action through its inhibitory effect upon PEP activity in plasma. S 17092 exhibited central effects, as evidenced by EEG recording in healthy volunteers, and could improve a delayed verbal memory task. Collectively, the preclinical and clinical effects of S 17092 have suggested a promising role for this compound as an agent for the treatment of cognitive disorders associated with cerebral aging.
Galantamine — a Novel Cholinergic Drug with a Unique Dual Mode of Action for the Treatment of Patients with Alzheimer's Disease
Authors: Lilienfeld Sean 
Published: August 2010

ABSTRACTGalantamine hydrobromide is a tertiary alkaloid drug that has been developed and approved in a number of countries including the USA and several countries in Europe as a treatment for mild‐to‐moderate Alzheimer's disease (AD). Galantamine has a unique, dual mode of action. It is a reversible, competitive inhibitor of acetylcholinesterase (AChE), and is the only drug actively marketed for the treatment of AD with proven activity as an allosteric modulator of nicotinic acetylcholine receptors (nAChRs). This latter activity is thought to be particularly important since decreases in the expression and activity of nAChRs make a large contribution to the reduction in central cholinergic neurotransmission in patients with AD. Galantamine exhibits favorable pharmacokinetic characteristics including predictable linear elimination kinetics at the recommended maintenance doses (16 and 24 mg/day), a relatively short half‐life (approximately 7 h) and high bioavailability. It is extensively metabolized in numerous pathways, mainly in the liver via cytochrome P450 enzymes CYP2D6 and CYP3A4, and has a low potential for clinically significant drug‐drug interactions. During four large randomized, double‐blind, placebo‐controlled trials of up to 6 months duration, galantamine 16 and 24 mg/day significantly benefited cognitive and global function, ability to perform activities of daily living (ADL) and behavior, relative to placebo and baseline, for up to 6 months. Caregiver burden (time spent by caregivers supervising patients or assisting them with ADL), and caregiver distress (related to patients' behavioral symptoms) were also reduced. Cognitive and functional abilities were preserved at or near baseline for at least 12 months in patients who received galantamine 24 mg/day for 12 months in a long‐term US study. These benefits were maximized by early and continued galantamine treatment and, again, were associated with significant reductions in caregiver burden. Trials of the efficacy of galantamine in dementia related to cerebrovascular disease have also yielded positive results. There are no safety concerns associated with the use of galantamine. The incidence of adverse events, particularly cholinergically mediated events affecting the gastrointestinal system, is generally low and can be minimized using the recommended slow dose‐escalation scheme. Galantamine may, therefore, help to reduce the overall burden and cost involved in caring for dementia patients. Taking all evidence into account, galantamine has the potential to become a first‐line therapy for dementia.
Negative Allosteric Modulation of AMPA‐preferring Receptors by the Selective Isomer GYKI 53784 (LY303070), a Specific Non‐competitive AMPA Antagonist
Authors: Ruel Jérôme , Guitton Matthieu J. , Puel Jean‐Luc 
Published: August 2010

ABSTRACTGYKI 53784 or LY303070 [(–)1‐(4‐aminophenyl)‐4‐methyl‐7,8‐methylenedioxy‐4,5‐dihydro‐3‐methylcarbamoyl‐2,3‐benzodiazepine] belongs to a new family of 2,3‐benzodiazepine compounds (also called homophtalazines) selective and non‐competitive antagonists at α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionate (AMPA) receptors. These compounds include the original GYKI‐52466, its more potent derivative GYKI 53655 and the active isomer of the latter, GYKI 53784. This review summarizes current knowledge of this novel AMPA antagonist: GYKI 53784.GYKI 53784 is the most potent of the compounds in the 2,3‐benzodiazepine class, blocking AMPA receptor‐mediated responses. In contrast to the compounds of the quinoxalinedione family, that block AMPA as well as kainate receptors, GYKI 53784 does not block the activation of kainate receptors. Furthermore, GYKI 53784 does not act at the same receptor site as positive AMPA modulators (i.e., cyclothiazide, BDP‐12, 1‐BCP or aniracetam). GYKI 53784 is a powerful neuroprotective agent in bothin vitroandin vivomodels of AMPA receptor‐mediated excitotoxicity.In contrast to NMDA receptor antagonists, whose favorable clinical actions are compromised by important side effects such as the impairment of memory functions, the selective AMPA antagonist, GYKI 53784, may be of potential clinical value, both in acute (stroke and trauma) and chronic (Alzheimer's disease, epilepsy) neurological disorders.
Moclobemide: Evolution, Pharmacodynamic, and Pharmacokinetic Properties
Authors: Bonnet Udo 
Published: August 2010

ABSTRACTThe benzamide moclobemide is a reversible inhibitor of monoamine‐oxidase‐A (RIMA). It has been extensively evaluated in the treatment of a wide spectrum of depressive disorders and less extensively in anxiety disorders. While clinical aspects will be presented in a subsequent review, this article focuses primarily on moclobemide's evolution, pharmacodynamic and pharmacokinetic properties. In particular, the effects on neurotransmission and intracellular signal transduction, the neuroendocrine system, the tyramine pressure response and animal models of depression are surveyed. In addition, other CNS effects are reviewed with special respect to experimental serotonergic syndrome, anxiolytic and antinociceptive activity, sleep, cognition and driving performance, neuroprotection and seizures.
BMS‐204352: A Potassium Channel Opener Developed for the Treatment of Stroke
Authors: Jensen Bo Skaaning 
Published: August 2010

ABSTRACTDuring ischemic stroke, a fatal biochemical cascade that results in neuronal hyperexcitability is initiated when neurons at risk are exposed to excessive excitatory amino acids and pathologically high levels of intracellular calcium (Ca2+). Therefore, neuroprotectants including NMDA‐antagonists and blockers of voltage‐gated Ca2+channels have been proposed as novel strategies for stroke treatment. Since potassium channels are key players in the control of neuronal excitability, and activation of neuronal potassium channels decrease excitability and neurotransmitter release, a novel approach for targeting acute ischemic stroke has been to develop openers of neuronal potassium channels. Bristol‐Myers Squibb is developing BMS‐204352, a fluoro‐oxindole potassium channel opener, as a potential neuroprotectant for the treatment of acute ischemic stroke. BMS‐203252 is a potent and effective opener of two important subtypes of neuronal potassium channels, the calcium‐activated, big‐conductance potassium channels (KCachannels) and voltage‐dependent, non‐inactivating potassium channels known as KCNQ channels. BMS‐204352 (0.3 mg/kg, i.v.) significantly reduced cortical infarct volume in a model of permanent occlusion of the middle cerebral artery (MCA) in spontaneous hypertensive rats (SHR), as compared to vehicle when administered 2 h post‐occlusion. At doses from 1 μg/kg to 1 mg/kg i.v., BMS‐204352 produced a significant reduction in cortical infarct volume in normotensive Wistar rats. In healthy humans, single and multiple i.v. doses of BMS‐204352 (0.001 to 0.2 mg/kg) were safe, well‐tolerated and without psychomotor function effects. Multiple doses of BMS‐204352 (0.1–2 mg/kg i.v.) administered within 48 h after stroke onset were well tolerated in patients in Phase II studies, designed to evaluate safety, tolerability and pharmacokinetics. No clinically significant differences in organ toxicity or adverse effects were found, and total clearance and volume of distribution were independent of dose. BMS‐204352 failed to show superior efficacy in acute stroke patients compared to placebo in a Phase III study that included 1978 patients at 200 centers worldwide.
Buprenorphine: An Analgesic with an Expanding Role in the Treatment of Opioid Addiction
Authors: Robinson Susan E. 
Published: August 2010

ABSTRACTBuprenorphine, a long‐acting opioid with both agonist and antagonist properties, binds to μ‐opioid (OP3), σ‐opioid (OP2), δ‐opioid (OP1), and nociceptin (ORL‐1) receptors. Its actions at these receptors have not been completely characterized, although buprenorphine is generally regarded as a μ‐opioid receptor partial agonist and a k‐opioid receptor antagonist. Its pharmacology is further complicated by an active metabolite, norbuprenorphine. Although buprenorphine can be used as an analgesic agent, it is of greater importance in the treatment of opioid abuse. Because of its partial agonist activity at μ‐opioid receptors and its long half‐life, buprenorphine has proven to be an excellent alternative to methadone for either maintenance therapy or detoxification of the opioid addict. Although buprenorphine may ultimately prove to be superior to methadone in the maintenance of the pregnant addict, its effects on the developing fetus must be carefully evaluated.
Nicotinic Cholinergic Modulation: Galantamine as a Prototype
Authors: Woodruff‐Pak Diana S. , Lander Cynthia , Geerts Hugo 
Published: August 2010

ABSTRACTNicotinic acetylcholine receptor pharmacology is becoming increasingly important in the clinical symptomatology of neurodegenerative diseases in general and of cognitive and behavioral aspects in particular. In addition, the concept of allosteric modulation of nicotinic acetylcholine receptors has become a research focus for the development of therapeutic agents. In this review the scientific evidence for changes in nicotinic acetylcholine receptors in Alzheimer's disease is described. Within this context, the pharmacology of galantamine, a recently approved drug for cognition enhancement in Alzheimer's disease, is reviewed along with preclinical studies of its efficacy on learning and memory. Galantamine modestly inhibits acetylcholinesterase and has an allosteric potentiating ligand effect at nicotinic receptors. The data collected in this review suggest that the unique combination of acetylcholinesterase inhibition and nicotinic acetylcholine receptor modulation offers potentially significant benefits over acetylcholinesterase inhibition alone in facilitating acetylcholine neurotransmission.
The Pharmacology of CP‐154,526, a Non‐Peptide Antagonist of the CRH1 Receptor: A Review
Authors: Seymour Patricia A. , Schmidt Anne W. , Schulz David W. 
Published: August 2010

ABSTRACTSince CRH has been shown to mediate stress‐induced physiological and behavioral changes, it has been hypothesized that CRH receptor antagonists may have therapeutic potential in disorders that involve excessive CRH activity. CP‐154,526 and its close analog antalarmin are potent, brain‐penetrable, selective nonpeptide CRH1 receptor antagonists that were discovered in an effort to develop compounds with efficacy in CNS disorders precipitated by stress. Since its discovery many investigators have used CP‐154,526 as a tool to study the pharmacology of CRH and its receptors and to evaluate its therapeutic potential in a variety of CNS and peripheral disorders. Systemically‐administered CP‐154,526 has been demonstrated to antagonize CRH‐ and stress‐induced neuroendocrine, neurochemical, electrophysiological, and behavioral effects.These findings support the hypothesis that CRH1 receptor antagonists may have therapeutic utility in a number of neuropsychiatric disorders. CP‐154,526, as well as other CRH1 receptor antagonists that have since been discovered, have also shown activity in several preclinical models of anxiety, depression, and substance abuse, while having little effect on locomotor activity and motor function. Although these effects are on occasion inconsistent among different laboratories, clinical evaluation of CRH 1 antagonists appears justified on the basis of these and clinical data implicating the involvement of CRH in several CNS disorders. The effects of CRH 1 antagonists on cognition, neurodegeneration, inflammation, and the gastrointestinal system have not been as extensively characterized and additional studies will be necessary to evaluate their therapeutic potential in these areas.
A Review of the Properties of Spiradoline: A Potent and Selective k‐Opioid Receptor Agonist
Authors: Wadenberg M‐L. G. 
Published: August 2010

ABSTRACTThe selective k‐opioid receptor agonist spiradoline mesylate (U62,066E), an arylacetamide, was synthesized with the intention of creating an analgesic that, while still retaining its analgesic properties, would be devoid of the, mainly μ receptor mediated, side effects such as physical dependence and respiratory depression associated with morphine. Spiradoline is highly selective for the k receptor withKiof 8.6 nM in guinea pig. Examination of the enantiomers of spiradoline, showed the (–)enantiomer to be responsible for the k agonist properties. Spiradoline easily penetrates the blood brain barrier, and does not seem to have any significant active metabolites. In preclinical studies, spiradoline has a short duration of action with a peak at around 30 min after administration.The analgesic properties of spiradoline are well documented in mice and rats. Antitussive properties have also been reported in rats. Furthermore, spiradoline was reported to display effects suggestive of neuroprotective properties in animal models of ischemia. In humans, spiradoline is a potent diuretic. It also produces significant sedation presumably due to its antihistamine properties. Preclinical studies have shown that spiradoline reduces blood pressure and heart rate, and has possible antiarrhythmic properties. Clinical studies did not confirm these findings.k Receptors inhibit dopaminergic neurotransmission. Spiradoline, given systematically to rats, produces a significant and long lasting decrease in dopamine release, and in loco‐motor activity. It has also antipsycho tic‐like effect in animal behavioral tests. At low doses spiradoline was reported to decrease tics in patients with Tourette's syndrome. Although spiradoline had promising effects in animal tests of analgesia, and a reasonably good safety profile in preliminary studies, it did not replace morphine as an analgesic. The available clinical data suggest that spiradoline produces disturbing adverse effects such as diuresis, sedation, and dysphoria at doses lower than those needed for analgesic effects. Thus, future development of spiradoline‐like analgesic compounds should preferably focus on reduction of unwanted effects on the central nervous system.Spiradoline, which currently is commercially available for preclinical research, might prove useful in some psychiatric conditions and possibly as a neuroprotective agent.
The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease
Authors: Rogawski Michael A. , Wenk Gary L. 
Published: August 2010

ABSTRACTMemantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase inhibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand‐gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory. However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons. Blockade of NMDA receptors by memantine could theoretically confer disease‐modifying activity in AD by inhibiting the “weak” NMDA receptor‐dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia. Moreover, recentin vitrostudies suggest that memantine abrogates β‐amyloid (Aβ) toxicity and possibly inhibits Aβ production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists, particularly those that act by a similar channel blocking mechanism such as dissociative anesthetic‐like agents (phencyclidine, ketamine, MK‐801). A variety of channel‐level factors could be relevant, including fast channel‐blocking kinetics and strong voltage‐dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate — an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity — while sparing synaptic responses required for normal behavioral functioning, cognition and memory.
The Promises and Pitfalls of Reboxetine
Authors: Page Michelle E. 
Published: August 2010

ABSTRACTThe antidepressant compound, morpholine, 2‐[(2‐ethoxyphenoxy)phenylmethyl]‐, methanesulfonate, or reboxetine, is a selective noradrenergic reuptake inhibitor that acts by binding to the norepinephrine (NE) transporter and blocking reuptake of extracellular NE back into terminals. This compound has low affinity for other transporters and receptors. The development of reboxetine as a potential antidepressant stems from the prior demonstration that blockade of the NE transporter imparts antidepressant activity. Desipramine, lofepramine, and nortryptiline are examples of tricyclic antidepressant (TCA) compounds from the first generation of antidepressants that exert their effects by blockade of NE reuptake. Maprotiline, a non‐tricyclic compound, is also a NE selective reuptake inhibitor. Unfortunately, these antidepressants are also associated with interactions with muscarinic, histaminergic, and adrenergic receptors, which are known to contribute to a variety of untoward side effects. Despite the positive pharmacological profile of reboxetine, i.e., selectivity and specificity, with relatively fewer side effects, its use as an antidepressant is currently limited to Europe. Reboxetine is marketed as Edronax in the UK, Norebox in Italy, and as Irenor in Spain. It is registered in Germany, Sweden, Denmark, Ireland, Austria and Finland. Based on studies conducted primarily outside the US, the FDA granted a preliminary letter of approval in 1999. However, more recent clinical studies conducted in the US and Canada, prompted by the FDA, resulted in a letter of non‐approval. To date, it is unclear why the further development of reboxetine as an antidepressant in the US has been halted. Despite this setback, reboxetine has been a valuable pharmacological tool to assess the role of the noradrenergic system in preclinical studies of depressive disorder.
Review of the Pharmacological and Clinical Profile of Rimcazole
Authors: Gilmore Deborah L. , Liu Yun , Matsumoto Rae R. 
Published: August 2010

ABSTRACTRimcazole is a carbazole derivative that acts in part as a σ receptor antagonist. Wellcome Research Laboratories introduced this compound during the 1980s when it was hypothesized to be a novel antipsychotic with an improved side effect profile. However, subsequent clinical trials demonstrated that rimcazole lacked efficacy in schizophrenic patients and it is now primarily used as an experimental tool. In addition to its actions as a σ receptor antagonist, rimcazole also has high affinity for dopamine transporters, and in recent years it has served as a lead compound for the development of novel dopamine transporter ligands. Although rimcazole cannot be considered a selective ligand for σ receptors, the recent development of other selective agonists and antagonists for σ receptors have aided in clarifying the involvement of these receptors in the actions of rimcazole. Many of the physiological and behavioral effects of rimcazole can in fact be ascribed to its action as a σ receptor antagonist, although there are exceptions. Rimcazole is likely to have a continued role in elucidating σ receptor function in eitherin vitroorin vivosystems where σ receptor‐mediated effects can be studied independently of the influence of dopamine and serotonin transporters.