bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adrogolide HCl (ABT‐431; DAS‐431), a Prodrug of the Dopamine D1Receptor Agonist, A‐86929: Preclinical Pharmacology and Clinical Data
Authors: Giardina William J. , Williams Michael 
Published: August 2010

ABSTRACTAdrogolide (ABT‐431; DAS‐431) is a chemically stable prodrug that is converted rapidly (<1 min) in plasma to A‐86929, a full agonist at dopamine D1receptors. Inin vitrofunctional assays, A‐86929 is over 400 times more selective for dopamine D1than D2receptors. In rats with a unilateral loss of striatal dopamine, A‐86929 produces contralateral rotations that are inhibited by dopamine D1but not by dopamine D2receptor antagonists. Adrogolide improves behavioral disability and locomotor activity scores in MPTP‐lesioned marmosets, a model of Parkinson's disease (PD), and shows no tolerance upon repeated dosing for 28 days.In PD patients, intravenous (i.v.) adrogolide has antiparkinson efficacy equivalent to that of L‐DOPA with a tendency towards a reduced liability to induce dyskinesia. The adverse events associated with its use were of mild‐to‐moderate severity and included injection site reaction, asthenia, headache, nausea, vomiting, postural hypotension, vasodilitation, and dizziness.Adrogolide can also attenuate the ability of cocaine to induce cocaine‐seeking behavior and does not itself induce cocaine‐seeking behavior in a rodent model of cocaine craving and relapse. In human cocaine abusers, i.v. adrogolide reduces cocaine craving and other cocaine‐induced subjective effects. The results of animal abuse liability studies indicate that adrogolide is unlikely to have abuse potential in man. Adrogolide has also been reported to reverse haloperidol‐induced cognitive deficits in monkeys, suggesting that it may be an effective treatment for the cognitive dysfunction associated with aging and disease.Adrogolide undergoes a high hepatic “first‐pass” metabolism in man after oral dosing and, as a result, has a low oral bioavailability (±4%). This limitation may potentially be circumvented by oral inhalation formulations for intrapulmonary delivery that greatly increase the bioavailability of adrogolide. As the first full dopamine D1receptor agonist to show efficacy in PD patients and to reduce the craving and subjective effects of cocaine in cocaine abusers, adrogolide represents an important tool in understanding the pharmacotherapeutic potential of dopamine D1receptor agonists.
Eptastigmine: Ten Years of Pharmacology, Toxicology, Pharmacokinetic, and Clinical Studies
Authors: Braida Daniela , Sala Mariaelvina 
Published: August 2010

ABSTRACTEptastigmine (heptyl‐physostigmine tartrate) is a carbamate derivative of physostigmine in which the carbamoylmethyl group in position 5 of the side chain has been substituted with a carbamoylheptyl group.In vitroandex vivoresults suggest that eptastigmine has a long‐lasting reversible brain cholinesterase (i.e., acetylcholinesterase and butyrylcholinesterase) inhibitory effect. When administeredin vivoto rodents by various routes, eptastigmine inhibits cerebral acetylcholinesterases (AChE) and increases acetylcholine (Ach) brain levels by 2500–3000%, depending on the dose. This effect leads to an improvement in the cerebral blood flow in the ischemic brain, excitatory and inhibitory effects on the gastrointestinal tract and to a protection from acute soman and diisopropylflu‐orophosphate intoxication.Eptastigmine, by either acute or chronic administration, has been found to have memory enhancing effects in different species of normal, aged and lesioned animals. It also restored to normal the age‐related increase of EEG power without affecting spontaneous motor activity.Clinical investigations on more than 1500 patients with Alzheimer's disease demonstrated that eptastigmine significantly improved cognitive performance (as assessed by the cognitive subscale of the Alzheimer's Disease Assessment Scale) as compared with placebo. This improvement was most evident in patients with more severe cognitive impairment at the baseline. The relationship between patient performance and average steady‐state AChE inhibition was described by an inverted U‐shaped dose‐response curve.Pharmacokinetic studies have revealed that after oral administration eptastigmine is rapidly distributed to the tissues and readily enters the CNS, where it can be expected to inhibit AChE for a prolonged period.Eptastigmine is generally well tolerated and the majority of adverse events (cholinergic) were mild to moderate in intensity. However, the adverse hematologic (granulocytopenia) effects reported in two studies have resulted in the suspension of further clinical trials.
Aniracetam: Its Novel Therapeutic Potential in Cerebral Dysfunctional Disorders Based on Recent Pharmacological Discoveries
Authors: Nakamura Kazuo 
Published: August 2010

ABSTRACTAniracetam is a pyrrolidinone‐type cognition enhancer that has been clinically used in the treatment of behavioral and psychological symptoms of dementia following stroke and in Alzheimer's disease. New discoveries in the behavioral pharmacology, biochemistry and pharmacokinetics of aniracetam provided new indications for this drug in the treatment of various CNS disorders or disease states. This article reviews these new findings and describes the effects of aniracetam in various rodent models of mental function impairment or cerebral dysfunction. Also, several metabolites of aniracetam have been reported to affect learning and memory in animals. It is, therefore, conceivable that major metabolites of aniracetam contribute to its pharmacological effects. The animal models, used in pharmacological evaluation of aniracetam included models of hypo attention, hypovigilance‐arousal, impulsiveness, hyperactivity, fear and anxiety, depression, impaired rapid‐eye movement sleep, disturbed temporal regulation, behavioral performance, and bladder hyperactivity. These are models of clinical disorders or symptoms that may include personality disorders, anxiety, depression, posttraumatic stress disorder, attentiondeficit/hyperactivity disorder, autism, negative symptoms of schizophrenia, and sleep disorders. At present, there is no convincing evidence that promising effects of aniracetam in the animal models will guarantee its clinical efficacy. It is conceivable, however, that clinical trials will demonstrate beneficial effects of aniracetam in the above listed disease states. New findings regarding the mechanism of action of aniracetam, its central target sites, and its effects on signal transduction are also discussed in this review article.
Pharmacology of Flibanserin
Authors: Borsini Franco , Evans Kennett , Jason Kathryn , Rohde Frank , Alexander Barbara , Pollentier Stephan 
Published: August 2010

ABSTRACTFlibanserin has preferential affinity for serotonin 5‐HT1A, dopamine D4, and serotonin 5‐HT2Areceptors.In vitroand in microiontophoresis, flibanserin behaves as a 5‐HT1Aagonist, a very weak partial agonist on dopamine D4receptors, and a 5‐HT2Aantagonist.In vivoflibanserin binds equally to 5‐HT1Aand 5‐HT2Areceptors. However, under higher levels of brain 5‐HT (i.e., under stress), flibanserin may occupy 5‐HT2Areceptors in higher proportion than 5‐HT1Areceptors. The effects of flibanserin on adenylyl cyclase are different from those of buspirone and 8‐OH‐DPAT, two other purported 5‐HT1Areceptor agonists. Flibanserin reduces neuronal firing rate in cells of the dorsal raphe, hippocampus, and cortex with the CA1 region being the most sensitive in the brain. Flibanserin‐induced reduction in firing rate in the cortex seems to be mediated through stimulation of postsynaptic 5‐HT1Areceptors, whereas the reduction of the number of active cells seems to be mediated through dopamine D4receptor stimulation. Flibanserin quickly desensitizes somatic 5‐HT autoreceptors in the dorsal raphe and enhances tonic activation of postsynaptic 5‐HT1Areceptors in the CA3 region. Flibanserin preferentially reduces synthesis and extracellular levels of 5‐HT in the cortex, where it enhances extracellular levels of NE and DA. Flibanserin displays antidepressant‐like activity in most animal models sensitive to antidepressants. Such activity, however, seems qualitatively different from that exerted by other antidepressants. Flibanserin seems to act via direct or indirect stimulation of 5‐HT1A, DA, and opioid receptors in those animal models. Flibanserin does not display consistent effects in animal models of anxiety and seems to exert potential antipsychotic effects. Flibanserin may induce some sedation but does not induce observable toxic effects at pharmacologically relevant doses.
SL651498, a GABAAReceptor Agonist with Subtype‐Selective Efficacy, as a Potential Treatment for Generalized Anxiety Disorder and Muscle Spasms
Authors: Griebel Guy , Perrault Ghislaine , Simiand Jacques , Cohen Caroline , Granger Patrick , Depoortere Henri , Françon Dominique , Avenet Patrick , Schoemaker Hans , Evanno Yannick , Sevrin Mireille , George Pascal , Scatton Bernard 
Published: August 2010

ABSTRACTSL651498 (6‐fluoro‐9‐methyl‐2‐phenyl‐4‐(pyrrolidin‐1‐yl‐carbonyl)‐2, 9‐dihydro‐1H‐pyrido[3,4‐b]indol‐1‐one) was identified as a drug development candidate from a research program designed to discover subtype‐selective GABAAreceptor agonists for the treatment of generalized anxiety disorder and muscle spasms. The drug displays high affinity for rat native GABAAreceptors containing α1(Ki= 6.8 nM) and α2(Ki= 12.3 nM) subunits, and weaker affinity for α5‐containing GABAAreceptors (Ki= 117 nM). Studies on recombinant rat GABAAreceptors confirm these findings and indicate intermediate affinity for the α3β2γ2subtype. SL651498 behaves as a full agonist at recombinant rat GABAAreceptors containing α2and α3subunits, and as a partial agonist at recombinant GABAAreceptors expressing α1and α5subunits. SL651498 produced anxiolytic‐like and skeletal muscle relaxant effects qualitatively similar to those of benzodiazepines (BZs) [minimal effective dose (MED): 1 to 10 mg/kg, i.p. and 3 to 10 mg/kg, p.o.]. However, unlike these latter drugs, SL651498 induced muscle weakness, ataxia or sedation at doses much higher than those having anxiolytic‐like activity (MED: 30 to 100 mg /kg, i.p. or p.o.). Moreover, in contrast to BZs, SL651498 did not produce tolerance to its anticonvulsant activity or physical dependence. It was much less active than BZs in potentiating the depressant effects of ethanol or impairing cognitive processes in rodents. The differential profile of SL651498 as compared to BZs may be related to its selective efficacy at the α2and α3‐containing GABAAreceptors. This suggests that selectively targeting GABAAreceptor subtypes can lead to drugs with increased clinical specificity. SL651498 represents a promising alternative to agents currently used for the treatment of anxiety disorders and muscle spasms without the major side effects seen with classical BZs.
BP 897, a Selective Dopamine D3Receptor Ligand with Therapeutic Potential for the Treatment of Cocaine‐Addiction
Authors: Garcia‐Ladona F. J. , Cox B. F. 
Published: August 2010

ABSTRACTBP 897 is a potent (Ki= 0.92 nM) dopamine D3receptor compound developed for the treatment of cocaine abuse and craving. BP 897 has a high selectivity for the dopamine D3versus D2receptors (70‐fold) and a moderate affinity for 5‐HT1Areceptors, (Ki= 84 nM), adrenergic‐α1 (Ki= 60 nM) and ‐α2adrenoceptors (Ki= 83 nM). BP 897 displays significant intrinsic activity at the human dopamine D3receptor by decreasing forskolin‐stimulated cAMP levels and by stimulating mitogenesis of dopamine D3‐expressing NG108–15 cells. Although these findings suggest that BP 897 is a partial agonist, recent studies in Chinese Hamster Ovary (CHO) cells with expressed dopamine D3receptors demonstrated that BP 897 is devoid of any intrinsic activity but potently inhibits dopamine agonist effects (pIC50= 9.43 and 9.51) in agonist‐induced acidification rate or increase of GTPγS binding, respectively. In addition, BP 897 inhibitsin vivo(EC50= 1.1 mg/kg, i.v.) agonist‐induced decrease of firing rate of dopaminergic neurons in the substantia nigra.It has been clearly shown that BP 897, 1 mg/kg, i.p., reduces cocaine‐seeking behavior in rats, without producing reinforcement on its own. In rhesus monkeys, BP 897 is not self‐administered (up to 30 μg/kg, i.v.) but reduces cocaine self‐administration. The potential usefulness of BP 897 in the treatment of drug‐seeking behavior is further supported by its effects in drug conditioning models. Although BP 897 reduces L‐DOPA‐induced dyskinesia in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated monkeys, it provokes a return of parkinsonian symptoms. At high doses BP 897 has been reported to produce catalepsy in rats. Pharmacokinetic and toxicological data have not yet been published. These interesting preclinical findings with BP 897 provide additional validation for dopamine D3receptor as a therapeutic target for the treatment of cocaine abuse and its associated central nervous system (CNS) disorders. BP 897 recently entered phase II clinical studies.
Pharmacology of Acamprosate: An Overview
Authors: Zornoza Teodoro , Cano María J. , Polache Ana , Granero Luis 
Published: August 2010

ABSTRACTIn the last years important advances have been made in the development of drugs for the treatment of alcohol addiction. Acamprosate (calcium bis‐acetylhomotaurine) is one of the better established drugs in this field on the European market. This review focuses first on the pharmacokinetics of acamprosate. The published data and the recent advances in our knowledge on the mechanisms involved in the intestinal absorption and elimination of this drug are summarized. The importance of pharmacokinetics for the proper clinical use of acamprosate is highlighted. The anti‐relapse as well as the well‐known effects of acamprosate on ethanol intake are discussed. The recent experiments in animal models of conditioned withdrawal are reviewed. These experiments, explored for the first time the anticraving effect of the drug. Finally, the proposed hypotheses on the neuropharmacological mechanism of action of acamprosate are discussed. The discussion deals with the relative importance of various hypotheses as well as with the recent experiments that support them. It is pointed out that further research is necessary in order to clearly understand the mode of action of acamprosate as well as the neurobiological mechanisms involved in alcohol dependence.
The Neuropsychopharmacology and Toxicology of 3,4‐methylenedioxy‐N‐ethyl‐amphetamine (MDEA)
Authors: Freudenmann Roland W. , Spitzer Manfred 
Published: August 2010

ABSTRACTThis paper reviews the pharmacology and toxicology of 3,4‐methylenedioxy‐N‐ethyl‐amphetamine (MDEA, “eve”). MDEA is a ring‐substituted amphetamine (RSA) like MDMA, its well known N‐methyl analog. Both have become very popular substances of abuse in the techno‐ and house‐music scene. They can evoke psychomotor stimulation, mild alterations of perception, sensations of closeness and a positive emotional state as well as sympathomimetic physical effects. At present, the name “ecstasy” is no longer used only for MDMA, but for the whole group of RSAs (MDA, MDMA, MDEA and MBDB) as they are chemically and pharmacologically nearly identical; moreover, many ecstasy pills contain mixtures of the RSAs. Hence, for a selective review on MDEA, it is crucial to strictly differentiate between: 1) street and chemical names, and 2) studies with or without chemically defined substances. In order to present MDEA‐specific information, the pharmacodynamics and kinetics are described on the basis of MDEA challenge studies in animals and humans. In the toxicology section, we present a collection of case reports on fatalities where MDEA was toxicologically confirmed. On the question of serotonergic neurotoxicity and possible long‐term consequences, however, MDEA‐specific information is available from animal studies only. The neurotoxic potential of MDEA in humans is difficult to estimate, as ecstasy users do not consume pure substances. For future research, challenge studies in animals using dosing regimens adapted to human consumption patterns are needed. Such challenge studies should directly compare individual RSAs. They will represent the most viable and fruitful approach to the resolution of the highly controversial issues of serotonergic neurotoxicity and its functional consequences.
Antinociceptive Properties of Fadolmidine (MPV‐2426), a Novel α2‐Adrenoceptor Agonist
Authors: Pertovaara Antti 
Published: August 2010

ABSTRACTFadolmidine (MPV‐2426) is a novel α2‐adrenoceptor (α2‐AR) agonist developed for spinal analgesia. It is highly selective for α2‐ARs, but it lacks subtype selectivity. Due to its pharmacokinetic properties, it only poorly penetrates blood‐brain barrier or spreads from the site of injection within the central nervous system. By intrathecal (i.t.) administration to laboratory animals, fadolmidine produces dose‐dependent antinociception in healthy controls and in models of inflammatory, postoperative and neuropathic pain. Fadolmidine has been effective against various submodalities of pain such as heat pain, mechanical pain, and visceral pain. In general, the antinociceptive potency of fadolmidine, i.t., was equal to that of dexmedetomidine. At antinociceptive i.t. doses fadolmidine did not suppress motoneurons or responses to innocuous stimulation. It produced no hemody‐namic depression and considerably less sedation than dexmedetomidine. By peripheral administration fadolmidine had no or only a weak antinociceptive action, except following nerve injury, particularly that of the postganglionic sympathetic nerve fibers. Together these experimental animal studies indicate that i.t. administration of fadolmidine provides a segmentally restricted treatment of somatic and visceral pain, with only minor cardiovascular and sedative side effects. Additionally, peripheral administration of fadolmidine might provide a selective treatment for some hypersensitivity states that involve dysfunction of the sympathetic nervous system.
TC‐1734: An Orally Active Neuronal Nicotinic Acetylcholine Receptor Modulator with Antidepressant, Neuroprotective and Long‐Lasting Cognitive Effects
Authors: Gatto Gregory J. , Bohme G Andrees , Caldwell William S. , Letchworth Sharon R. , Traina Vincent M. , Obinu M. Carmen , Laville Michel , Reibaud Michel , Pradier Laurent , Dunbar Geoffrey , Bencherif Merouane 
Published: August 2010

ABSTRACTThe development of selective ligands targeting neuronal nicotinic acetylcholine receptors to alleviate symptoms associated with neurodegenerative diseases presents the advantage of affecting multiple deficits that are the hallmarks of these pathologies. TC‐1734 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal nicotinic receptors. Microdialysis studies indicate that TC‐1734 enhances the release of acetylcholine from the cortex. TC‐1734, by either acute or repeated administration, exhibits memory enhancing properties in rats and mice and is neuroprotective following excitotoxic insult in fetal rat brain in cultures and against alterations of synaptic transmission induced by deprivation of glucose and oxygen in hippocampal slices. At submaximal doses, TC‐1734 produced additive cognitive effects when used in combination with tacrine or donepezil. Unlike (‐)‐nicotine, behavioral sensitization does not develop following repeated administration of TC‐1734. Its pharmacokinetic (PK) profile (half‐life of 2 h) contrasts with the long lasting improvement in working memory (18 h) demonstrating that cognitive improvement extends beyond the lifetime of the compound. The very low acute toxicity of TC‐1734 and its receptor activity profile provides additional mechanistic basis for its suggested potential as a clinical candidate. TC‐1734 was very well tolerated in acute and chronic oral toxicity studies in mice, rats and dogs. Phase I clinical trials demonstrated TC‐1734's favorable pharmacokinetic and safety profile by acute oral administration at doses ranging from 2 to 320 mg.The bioavailability, pharmacological, pharmacokinetic, and safety profile of TC‐1734 provides an example of a safe, potent and efficacious neuronal nicotinic modulator that holds promise for the management of the hallmark symptomatologies observed in dementia.
ACEA 1021: Flip or Flop?
Authors: Petty Margaret A. , Weintraub Philip M. , Maynard Kenneth I. 
Published: August 2010

ABSTRACTInasmuch as glutamate is the main excitatory neurotransmitter in the central nervous system, strategies aimed at counteracting glutamate excitotoxicity, which is at least partially involved in many acute neurologic, chronic neurodegenerative and psychiatric diseases, are challenging. Blockade of the NMDA receptor was identified as one way of achieving selective antagonism and overcoming glutamate neurotoxicity, yet not without liabilities. Glycine site antagonism of the NMDA receptor in 1987 offered a significant advance in blocking this receptor because such drugs were shown to lack most of the side effects, such as memory impairment, ataxia, lack of motor coordination and psychotomimetic effects, which accompanied competitive and non‐competitive NMDA receptor antagonists. To date, much has been done to improve the structure‐activity relationship (SAR) of compounds resulting in the synthesis of ACEA 1021. It is unclear, however, whether further chemical substitutions will lead to an improved compound. Many studies have been performed with ACEA 1021 and although there are muchin vitroandin vivodata to support its neuroprotective effects and improved safety profile, there is very little published information regarding its clinical pharmacology. In order to properly evaluate the true potential for ACEA 1021 in acute and chronic CNS disorders additional longer term safety and efficacy data in humans are needed.