bluuebunny/crossref_metadata_2025 huggingface dataset:
Haem arginate infusion stimulates haem oxygenase‐1 expression in healthy subjects
Authors: Doberer D , Haschemi A , Andreas M , Zapf T‐C , Clive B , Jeitler M , Heinzl H , Wagner O , Wolzt M , Bilban M.
Published: August 2010

BACKGROUND AND PURPOSEHaem oxygenase 1 (HO‐1) is an inducible protein that plays a major protective role in conditions such as ischaemia‐reperfusion injury and inflammation. In this study, we have investigated the role of haem arginate (HA) in human male subjects in the modulation of HO‐1 expression and its correlation with the GT length polymorphism (GTn) in the promoter of the HO‐1 gene.

EXPERIMENTAL APPROACHIn a dose‐escalation, randomized, placebo‐controlled trial, seven healthy male subjects with a homozygous short (S/S) and eight with a long (L/L) GTngenotype received intravenous HA. HO‐1 protein expression and mRNA levels in peripheral blood monocytes, bilirubin, haptoglobin, haemopexin and haem levels were analysed over a 48 h observation period.

KEY RESULTSWe found that the baseline mRNA levels of HO‐1 were higher in L/L subjects, while protein levels were higher in S/S subjects. HA induced a dose‐dependent increase in the baseline corrected area under the curve values of HO‐1 mRNA and protein over 48 h. The response of HO‐1 mRNA was more pronounced in L/L subjects but the protein level was similar across the groups.

CONCLUSIONS AND IMPLICATIONHA is an effective inducer of HO‐1 in humans irrespective of the GTngenotype. The potential therapeutic application of HA needs to be evaluated in clinical trials.
6‐Shogaol, an active constituent of ginger, inhibits breast cancer cell invasion by reducing matrix metalloproteinase‐9 expression via blockade of nuclear factor‐κB activation
Authors: Ling H , Yang H , Tan S‐H , Chui W‐K , Chew E‐H
Published: August 2010

BACKGROUND AND PURPOSE Shogaols are reported to possess anti‐inflammatory and anticancer activities. However, the antimetastatic potential of shogaols remains unexplored. This study was performed to assess the effects of shogaols against breast cancer cell invasion and to investigate the underlying mechanisms.

EXPERIMENTAL APPROACH The anti‐invasive effect of a series of shogaols was initially evaluated on MDA‐MB‐231 breast cancer cells using the matrigel invasion assay. The suppressive effects of 6‐shogaol on phorbol 12‐myristate 13‐acetate (PMA)‐induced matrix metalloproteinase‐9 (MMP‐9) gelatinolytic activity and nuclear factor‐κB (NF‐κB) activation were further determined.

KEY RESULTS Shogaols (6‐, 8‐ and 10‐shogaol) inhibited PMA‐stimulated MDA‐MB‐231 cell invasion with an accompanying decrease in MMP‐9 secretion. 6‐Shogaol was identified to display the greatest anti‐invasive effect in association with a dose‐dependent reduction in MMP‐9 gene activation, protein expression and secretion. The NF‐κB transcriptional activity was decreased by 6‐shogaol; an effect mediated by inhibition of IκB phosphorylation and degradation that subsequently led to suppression of NF‐κB p65 phosphorylation and nuclear translocation. In addition, 6‐shogaol was found to inhibit JNK activation with no resulting reduction in activator protein‐1 transcriptional activity. By using specific inhibitors, it was demonstrated that ERK and NF‐κB signalling, but not JNK and p38 signalling, were involved in PMA‐stimulated MMP‐9 activation.

CONCLUSIONS AND IMPLICATIONS 6‐Shogaol is a potent inhibitor of MDA‐MB‐231 cell invasion, and the molecular mechanism involves at least in part the down‐regulation of MMP‐9 transcription by targeting the NF‐κB activation cascade. This class of naturally occurring small molecules thus have potential for clinical use as antimetastatic treatments.
Overview of the Pharmacological Features of Honokiol
Authors: Maruyama Yuji , Kuribara Hisashi
Published: August 2010

This paper provides an overview of the pharmacological features of honokiol (3′,5‐di‐2‐propenyl‐1,1′‐biphenyl‐2,4′‐diol), an isomer of neolignans isolated and identified from the stem bark of Magnoliaceous plants (Magnolia obovataThunb, Wa‐Koboku in Japanese). The magnolia bark has been utilized as a herbal remedy for the treatment of a wide variety of clinical disorders. Honokiol and magnolol (an isomer of honokiol) were recently identified as anxiolytic agents in the extracts of Saiboku‐to, an oriental herbal medicine (Kampo). Behavioral evaluation through an elevated plus‐maze test demonstrated that honokiol, 0.2–2 mg/kg, p.o., for 7 days, was at least 5000 times more potent than Saiboku‐to. Honokiol has a comparatively lower risk of causing benzodiazepine‐like side effects, such as central depression, muscle relaxation, amnesia, or physical dependence. In addition to these central actions, a wide variety of pharmacological effects and biochemical activities of honokiol have been reported during the past 10 years. The main effects, including the limited information regarding the metabolism and kinetics of the compound, are briefly introduced in this text. Information available on honokiol, including its specific and simple chemical structure, suggests the possibility of deriving more potent compounds in the drug design process.
Sipatrigine (BW 619C89) is a Neuroprotective Agent and a Sodium Channel and Calcium Channel Inhibitor
Authors: Hainsworth Atticus H. , Stefani Alessandro , Calabresi Paolo , Smith Terence W. , Leach Michael J.
Published: August 2010

Sipatrigine is a substituted pyrimidine derived from lamotrigine. It attenuates glutamate releasein vitroandin vivo, probably as a result of sodium and calcium channel inhibition. It consistently reduces cortical infarct volume in rodent models of global, permanent focal, and transient focal ischemia (typically 50–60% reduction with maximum effective doses >20 mg/kg). Striatal protection was found in some studies but not others. The drug was effective also in a rat optic nerve model of white matter ischemia, providing complete neuroprotection at the highest concentration (100 μM) used. In monkeys, CNS penetration by sipatrigine was rapid and the steady state brain/plasma ratio was >40. In humans, low doses (< 2 mg/kg, then 1 mg/kg/8 h) were well tolerated. At higher doses a significant incidence of hallucinations and vomiting was observed. These adverse effects were speculated to be due to interactions with muscarinic receptors and 5‐HT3(or sigma) receptors, respectively. Cardiovascular side effects appeared not to be a major concern. In electrophysiological studies, sipatrigine inhibited native neuronal sodium and calcium channels (including L, N, and P/Q type) and recombinant type IIA sodium and N and T type calcium channels, all with similar potency (IC50in the range 5–16 μM). Inhibitory potency was increased by high action potential firing frequencies and a depolarized resting voltage. These properties may account for its actionsin vitroand in animal models but do not exclude possible additional actions in later stages of ischemic damage.
SNX‐482: A Novel Class E Calcium Channel Antagonist from Tarantula Venom
Authors: Newcomb Robert , Chen Xiao‐hua , Dean Robin , Dayanithi Govindin , Cong Ruth , Szoke Balazs , Lemos Jose , Bowersox Scott , Miljanich George
Published: August 2010

Calcium channels are represented by at least 9 distinct genes (calcium channel classes A‐I), corresponding to at least 5 functional and pharmacological “types” (L, N, P/Q, R and T). Selective L‐, N‐, and T‐type channel antagonists are either in clinical use or in late stage clinical trials, while antagonists of P/Q channels are known to be toxic. No selective ligand has been identified for the R‐type (class E), and its function and pharmacology are consequently, poorly understood. We review recent work on the discovery and initial characterization of SNX‐482, the first known selective antagonist of R‐type calcium channels. SNX‐482 is a 41 residue acidic peptide with three disulfide bonds that has been isolated from the venom of the African tarantula,Hysterocrates gigas.In cell‐based assays, it is a potent and selective inhibitor of the class E or R‐type calcium channel. SNX‐482 blocks some but not all native R‐type currents: it blocks an R‐type current in vertebrate neurohypophysis, but it does not block an R‐type current in cerebellar granule cells. The peptide blocks oxytocin but not vasopressin release, suggesting a possible utility for SNX‐482 as a neuroendocrine modulator. The peptide possesses antiseizure activity in several animal models of epilepsy, suggesting that class E antagonists may have pharmacological use in seizure disorders.
Preclinical Pharmacology of ABT‐594: A Nicotinic Acetylcholine Receptor Agonist for the Treatment of Pain
Authors: Meyer Michael D. , Anderson David J. , Campbell Jeffrey E. , Carroll Sherry , Marsh Kennan C. , Rodrigues A. David , Decker Michael W.
Published: August 2010

ABT‐594 [(R)‐5‐(2‐azetedinylmethoxy)‐2‐chloropyridine mono‐tosylate salt] is a neuronal nicotinic acetylcholine receptor (nAChR) agonist with antinociceptive activity in rodent pain models. Whereas the binding affinity of ABT‐594 at α4β2‐containing nAChRs is comparable to that of (±)‐epibatidine, ABT‐594 has lower affinity than (±)‐epibatidine at α3‐containing nAChRs. Similarly, ABT‐594 is approximately equivalent to (±)‐epibatidine in a Ca2+flux assay in K‐177 cells that express 04132 nAChRs but less potent than (±)‐epibatidine in the IMR‐32 (α3‐containing) cell line. ABT‐594 is active in a variety of rodent models of acute thermal (mouse hot‐plate, rat thermal paw withdrawal), persistent chemical (mouse abdominal constriction, rat formalin) and neuropathic (diabetic neuropathy and Chung spinal nerve ligation in rats) pain. Effects of ABT‐594 on acute thermal pain appear to be mediated centrally and may involve activation of descending inhibition originating in the brainstem. ABT‐594 decreases responses of wide dynamic range neurons in the dorsal lumbar spinal cord to noxious thermal and mechanical stimuli but does not alter responses of these neurons to innocuous stimuli. ABT‐594 has plasma elimination half life ranging from < 0.5 h in mice to 4.7 h in dogs and readily penetrates the CNS. Oral bioavailability ranges from 35 to 80% in a variety of species. In rats, the majority of ABT‐594 is excreted in the urine after both oral and intravenous administration, and parent drug accounts for better than 75% of total radioactivity in plasma after administration of labeled ABT‐594 (AUC0–12)
A Novel Approach to the Identification of Psychiatric Drugs: Serotonin‐Glutamate Interactions in the Prefrontal Cortex
Authors: Marek Gerard J.
Published: August 2010

Activation of neocortical 5‐hydroxytryptamine2A(5‐HT2A) receptors is thought to mediate the profound psychomimetic effects of hallucinogenic drugs such as LSD and mescaline. These effects include alteration in mood, perception, and cognition. Conversely, blockade of neocortical 5‐HT2receptor may be related to the thymoleptic effects of newly released antidepressant (e.g., mirtazepine, nefazodone) and atypical antipsychotic drugs (e.g., risperidone, olanzapine). Therefore, one strategy to develop novel antidepressant drugs might be to identify drugs which suppress the effects of 5‐HT2Areceptor activation in key neurocircuits. Electrophysiological experiments usingin vitrorat slices of the medial prefrontal cortex have found that activation of 5‐HT2Areceptors results in glutamate release from thalamocortical terminals by a novel focal effect. A number of monoamine (5‐HT1/7, β2), metabotropic glutamate (mGlu2), and neuropeptide (μ‐opioid) receptors suppress the glutamate release induced by 5‐HT2Areceptor activation. Clinical studies examining the effects of serotonin or catecholamine depletion suggest the activation of 5‐HT or catecholamine receptors mediate the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs), respectively. In addition, opiate agonists may have antidepressant properties. Therefore, it is suggested that elucidation of the specific receptors that suppress glutamate release induced by 5‐HT2Areceptor activation in the medial prefrontal cortex may have several effects. First, this might lead to a more complete understanding of the 5‐HT receptor(s) that mediate the therapeutic effects of presently used drugs such as SSRIs. This site might be a therapeutic target free of side effects such as sexual dysfunction. Second, this strategy might lead to novel therapeutic targets for depression, such as metabotropic glutamate agonists which may not be efficacious in screening strategies primarily dependent on synaptic availability of monoaminergic neurotransmitters.
Genetically Epilepsy‐Prone Rats (GEPRs) in Drug Research
Authors: Jobe Phillip C. , Dailey John W.
Published: August 2010

Two independently derived, inbred strains of genetically epilepsy‐prone rats (GEPRs) have been developed, the moderately epileptic GEPR‐3 and the more severely epileptic GEPR‐9. Seizures expressed by GEPRs model human generalized tonic/clonic seizures (GTCSs) and partial seizures secondarily generalized to tonic/clonic seizures. Several types of existing antiepileptic drugs have been tested in the GEPR model. Without exception, the seizure suppressing properties of these drugs occur both in GEPR‐3 s and GEPR‐9s. The differential responses of the two GEPR strains separate the antiepileptic drugs into three categories: (1) those effective in GTCSs and partial seizures; (2) those that are additionally effective in absence seizures; and (3) those effective in absence seizures but not in convulsive seizures. No known false positives have yet been detected in GEPR tests. In addition to the utility of the seizures expressed by GEPRs in drug development paradigms, these animals also have potential in the search for drugs that are specifically “antiseizure predisposition” rather than merely anticonvulsant. Heretofore, worldwide drug development efforts have emphasized the discovery of drugs that are anticonvulsant in nonepileptic animals. As might have been anticipated, these same drugs have proven to be anticonvulsant in epileptic subjects. Paradigms that would detect drugs with the capacity to correct the biological determinants of predisposition are in early stages of application. Kindling seizures provide a means to identify drugs that might be useful in correcting stimulus‐induced seizure predisposition. The GEPR and other genetic models of the epilepsies provide models for developing treatments to correct genetically determined seizure predisposition. Emerging evidence supports the hypothesis that GEPRs model comorbidity between the epilepsies and affective disorders. Understanding the basis of this comorbidity has the potential to enable the development of treatments that reverse the underlying abnormalities of the coexisting disorders. Because human epilepsies and affective disorders are environmentally and genetically complex, the abnormalities of the GEPR probably will not account for all predispositions leading to this comorbidity.
2‐(2‐aminoethyl)‐quinoline (D‐1997): A Novel Agonist at Craniovascular 5‐HT1Receptors Relevant to Migraine Therapy
Authors: Terrón José A.
Published: August 2010

The functional pharmacological properties of a group of quinoline‐derivatives were screened for agonist activity at 5‐HT1‐like receptors mediating vasoconstriction. In experimental models predictive of antimigraine activity, 2‐(2‐aminoethyl) quinoline hydrochloride (D‐1997) exhibited higher potency and efficacy at vasoconstrictor 5‐HT1‐like receptors than quipazine. D‐1997 was also found to activate a novel vasoconstrictor mechanism in the carotid circulation. It is suggested D‐1997 may represent a useful lead in the search for better acute antimigraine therapies.
Pitrazepin: Interactions with Transmitter Receptors of the Central and Peripheral Nervous Systems
Authors: Demuro Angelo , Miledi Ricardo
Published: August 2010

Pitrazepin [3‐(piperazinyl‐1)‐9H‐dibenz(c.f)triazolo(4,5‐a)azepin], is an N‐aryl‐piperazine derivative, whose heterocyclic structure is similar to that of atypical antipsychotics like clozapine. This paper is an overview of the pharmacological actions of pitrazepin, with an emphasis on its actions on GABAAand glycine neurotransmitter receptors. Recent results on the antagonist actions of pitrazepin on acetylcholine (ACh) currents in oocytes expressing either rat neuronal or mouse muscle nicotinic acetylcholine receptors are presented. Many of the pharmacological features of the new‐generation antipsychotics have been derived from studies of structurally treated drugs. A detailed understanding of the ineractions of these drugs with neurotransmitter receptor is necessary to develop more effective antipsychotics.
BTS 72664 – A Novel CNS Drug With Potential Anticonvulsant, Neuroprotective, and Antimigraine Properties
Authors: Smith Sharon L. , Thompson Kevin S. J. , Sargent Bruce J. , Heal David J.
Published: August 2010

BTS 72664, (R)‐7‐[1‐(4‐chlorophenoxy)]ethyl]‐1,2,4‐triazolo(1,5‐α)pyrimidine, was identified as a drug development candidate from a research program designed to discover novel, broad‐spectrum, non‐sedative anticonvulsant drugs. BTS 72664 antagonized bicuculline (BIC)‐ and maximal electroshock (MES)‐induced convulsions with ED50values of 1.9 and 47.5 mg/kg p.o., respectively. In rodents, it has a wide spectrum of activity preventing seizures induced by picrotoxin, pentylenetetrazol, i.c.v. 4‐aminopyridine or NMD A, and audiogenic seizures in DBA‐2 mice and GEPR‐9 rats. BTS 72664 was also effective in preventing convulsions in amygdala‐kindled rats The lack of sedative potential was predicted on the basis of wide separation between ED50in anticonvulsant models and TD50for motor impairment in mice in rotating rod and inverted horizontal grid tests. BTS 72664 is likely to produce its anticonvulsant effect by enhancing chloride currents through picrotoxin‐sensitive chloride channels, and by weak inhibition of Na+and NMDA channels. It does not act, however, at the benzodiazepine binding site. In addition to its potential use in the treatment of epilepsy BTS 72664 may be useful in the treatment of stroke. At 50 mg/kg p.o. x 4, given to rats at 12 hourly intervals, starting at 15 min after permanent occlusion of middle cerebral artery (MCA), it reduced cerebral infarct size by 31% (measured at 2 days after insult) and accelerated recovery in a functional behavioral model. BTS 72664 prevented increases in extraneuronal concentrations of glutamate, glycine and serine brain levels induced by a cortical insult to rats (cf. cortical spreading depression). It may, therefore, have also antimigraine activity.
Pharmacology of the Atypical Antipsychotic Remoxipride, a Dopamine D2Receptor Antagonist
Authors: Nadal Roser
Published: August 2010

Remoxipride is a substituted benzamide that acts as a weak but very selective antagonist of dopamine D2receptors. It was introduced by Astra (Roxiam) at the end of the eighties and was prescribed as an atypical antipsychotic. This article reviews its putative selective effects on mesolimbic versus nigrostriatal dopaminergic systems. In animals, remoxipride has minimal cataleptic effects at doses that block dopamine agonist‐induced hyperactivity. These findings are predictive of antipsychotic activity with a low likelihood of extrapyramidal symptoms. Remoxipride also appears to be effective in more recent animal models of schizophrenia, such as latent inhibition or prepulse inhibition. In clinical studies, remoxipride shows a relatively low incidence of extrapyramidal side effects and its effects on prolactin release are short‐lasting and generally mild. The clinical efficacy of remoxipride is similar to that of haloperidol or chlorpromazine. Although its clinical use was severely restricted in 1993, due to reports of aplastic anemia in some patients receiving remoxipride, this drug has been found to exhibit relatively high selectivity for dopamine D2receptors making remoxipride an interesting tool for neurochemical and behavioral studies.
SCH 23390: The First Selective Dopamine D1‐Like Receptor Antagonist
Authors: Bourne James A.
Published: August 2010

SCH 23390, the halobenzazepine (R)‐(+)‐7‐chloro‐8‐hydroxy‐3‐methyl‐1‐phenyl‐2,3,4,5‐tetrahydro‐1H–3‐benzazepine, is a highly potent and selective dopamine D1‐like receptor antagonist with aKiof 0.2 and 0.3 nM for the D1and D5dopamine receptor subtypes, respectively.In vitro, it also binds with high affinity to the 5‐HT2and 5‐HT1Cserotonin receptor subtypes. However, the doses required to induce a similar responsein vivoare greater than 10‐fold higher than those required to induce a D1‐mediated response.

Previousin vivopharmacological studies with SCH 23390 have shown it to abolish generalized seizures evoked by the chemoconvulsants: pilocarpine and soman. These studies provide evidence of the potential importance of D1‐like dopaminergic receptor mechanisms in facilitating the initiation and spread of seizures. The inference from a majority of studies is that the activation of dopamine D1receptors facilitates seizure activity, whereas activation of D2receptors may inhibit the development of seizures. SCH 23390 has also been used in studies of other neurological disorders in which the dopamine system has been implicated, such as psychosis and Parkinson's disease. Apart from the study of neurological disorders, SCH 23390 has been extensively used as a tool in the topographical determination of brain D1receptors in rodents, nonhuman primates, and humans.

In summary, SCH 23390 has been a major tool in gaining a better understanding of the role of the dopamine system, more specifically the D1receptor, in neurological function and dysfunction.
SB‐236057‐A: A Selective 5‐HT1B Receptor Inverse Agonist
Authors: Roberts Claire , Watson Jeanette , Price Gary W. , Middlemiss Derek N.
Published: August 2010

5‐HT1B autoreceptors are involved in the control of extracellular 5‐HT levels from both the terminal and cell body regions of serotonergic neurons. In this manuscript we review the pharmacological and pharmacokinetic data available for the selective and potent 5‐HT1B receptor inverse agonist, SB‐236057‐A (1′‐ethyl‐5‐(2′‐methyl‐4′‐(5‐methyl‐1,3,4‐oxadiazolyl‐2‐yl)biphenyl‐4‐carbonyl)‐2,3,6,7‐tetrahydrospiro (furo[2,3‐f]indole‐3,4′‐piperidine) hydrochloride). SB 236057‐A has been shown to have high affinity for human 5‐HT1B receptors (pKi= 8.2) and displays 80 or more fold selectivity for the human 5‐HT1B receptor over other 5‐HT receptors and a range of additional receptors, ion channels and enzymes. In functional studies at human 5‐HT1B receptors SB‐236057‐A displayed inverse agonism (pA2= 8.9) using [35S]GTPγS binding, and silent antagonism (pA2= 9.2) using cAMP accumulation. SB‐236057‐A also acted as an antagonist at the 5‐HT terminal autoreceptor as measured by [3H]5‐HT release from electrically stimulated guinea pig and human cortical slices.

In the guinea pig, pharmacokinetic analysis demonstrated that SB‐236057‐A was bioavailable and according to in vivo pharmacodynamic assays it enters brain and has a long duration of action. Importantly no side effect liability was evident at relevant doses from anxiogenic, cardiovascular, sedative or migraine viewpoints.

In vivo microdialysis studies demonstrated that SB‐236057‐A is an antagonist in the guinea pig cortex but has no effect on extracellular 5‐HT levels per se. In contrast, SB‐236057‐A increased extracellular 5‐HT levels in the guinea pig dentate gyrus. This increase in 5‐HT release was comparable to that observed after 14 days of paroxetine administration.

SB‐236057‐A has been a useful tool in confirming that, in either guinea pigs or humans, the terminal 5‐HT autoreceptor is of the 5‐HT1B subtype. It appears that acute 5‐HT1B receptor blockade, by virtue of increased 5‐HT release in the dentate gyrus, may provide a rapidly acting antidepressant.
Phenibut (β‐Phenyl‐GABA): A Tranquilizer and Nootropic Drug
Authors: Lapin Izyaslav
Published: August 2010

Phenibut (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

Any 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

Galantamine 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.
Thirty‐first Annual Meeting of Society for Neuroscience San Diego, CA November 10–15, 2001
Authors: Scriabine Alexander
Published: August 2010

The 31st Meeting of the Society for Neuroscience took place November 10–15, 2001 in the San Diego Convention Hall, San Diego, CA. The total number of attendees exceeded 25,000. The meeting consisted of 986 scientific sessions, each with 10 to 30 presentations or posters. This report covers only oral presentations or posters on new drugs attended or viewed by the author of this report.
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

GYKI 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

The 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

During 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

Buprenorphine, 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

Nicotinic 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

Since 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

The 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 15th Annual Meeting of the Winter Conference on Neural Plasticity Guadeloupe, French Antilles February 23 – 28, 2003
Authors: Petit Ted L.
Published: August 2010

The 15th Annual Meeting of the Winter Conference on Neural Plasticity was held in Guadeloupe, French Antilles from February 23 – 28, 2003. The Conference was attended by approximately 80 participants from Canada, United Kingdom, Germany, Hungary, Italy, and the United States. Most of the participants were neuroscientists from universities and basic research departments of applied institutions. The primary focus of the conference is to annually review recent advances in the area of neural plasticity from multi‐disciplinary and lifespan perspectives. There were nine scientific sessions, each lasting two hours.
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

Memantine 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

The 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

Rimcazole 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.