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Article: Effects of the anticonvulsant lacosamide compared to valproate and lamotrigine on cocaine-enhanced reward in rats

Béguin, Cécile / Potter, David N / Carlezon, William A., Jr / Stöhr, Thomas / Cohen, Bruce M

Brain research. 2012 Oct. 15, v. 1479

2012

Abstract: Some drugs developed as anticonvulsants (notably, valproate and lamotrigine) have therapeutic effects in bipolar and related disorders. Lacosamide, a recently approved anticonvulsant, has unique effects on sodium channels that may play a role in ... ...

Abstract	Some drugs developed as anticonvulsants (notably, valproate and lamotrigine) have therapeutic effects in bipolar and related disorders. Lacosamide, a recently approved anticonvulsant, has unique effects on sodium channels that may play a role in producing the mood-stabilizing effects of anticonvulsant drugs. We tested whether lacosamide would have effects similar to or different from valproate and lamotrigine in a model of reward and elevated mood. The intracranial self-stimulation (ICSS) test is sensitive to the function of brain reward systems. Changes in ICSS may model aspects of disorders characterized by abnormalities of reward and motivation. Cocaine elevates mood, and reduction of cocaine-induced facilitation of ICSS has been used to predict antimanic-like or mood stabilizing effects of drugs. We tested lacosamide, lamotrigine, and valproate in the rat ICSS test alone or in the presence of cocaine. A high dose of lacosamide (30mg/kg) significantly elevated ICSS thresholds, indicating that it reduced the rewarding impact of medial forebrain bundle stimulation. Lower doses (3–10mg/kg) did not alter ICSS, but blocked the cocaine-induced lowering of ICSS thresholds. The highest doses of valproate (300mg/kg) and lamotrigine (30mg/kg) also elevated ICSS thresholds, and only these high doses significantly lowered cocaine-induced effects. Of the drugs tested, only lacosamide significantly attenuated the reward-facilitating effects of cocaine at doses that had no effects on ICSS response in the absence of cocaine. Abnormalities of mood and reward are common in psychiatric disorders, and these results suggest that lacosamide deserves further study in models of these disorders.
Keywords	anticonvulsants ; brain ; cocaine ; emotions ; models ; motivation ; rats ; sodium channels ; therapeutics
Language	English
Dates of publication	2012-1015
Size	p. 44-51.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2012.08.030
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Effects of the anticonvulsant lacosamide compared to valproate and lamotrigine on cocaine-enhanced reward in rats.

Béguin, Cécile / Potter, David N / Carlezon, William A / Stöhr, Thomas / Cohen, Bruce M

Brain research

2012 Volume 1479, Page(s) 44–51

Abstract	Some drugs developed as anticonvulsants (notably, valproate and lamotrigine) have therapeutic effects in bipolar and related disorders. Lacosamide, a recently approved anticonvulsant, has unique effects on sodium channels that may play a role in producing the mood-stabilizing effects of anticonvulsant drugs. We tested whether lacosamide would have effects similar to or different from valproate and lamotrigine in a model of reward and elevated mood. The intracranial self-stimulation (ICSS) test is sensitive to the function of brain reward systems. Changes in ICSS may model aspects of disorders characterized by abnormalities of reward and motivation. Cocaine elevates mood, and reduction of cocaine-induced facilitation of ICSS has been used to predict antimanic-like or mood stabilizing effects of drugs. We tested lacosamide, lamotrigine, and valproate in the rat ICSS test alone or in the presence of cocaine. A high dose of lacosamide (30 mg/kg) significantly elevated ICSS thresholds, indicating that it reduced the rewarding impact of medial forebrain bundle stimulation. Lower doses (3-10 mg/kg) did not alter ICSS, but blocked the cocaine-induced lowering of ICSS thresholds. The highest doses of valproate (300 mg/kg) and lamotrigine (30 mg/kg) also elevated ICSS thresholds, and only these high doses significantly lowered cocaine-induced effects. Of the drugs tested, only lacosamide significantly attenuated the reward-facilitating effects of cocaine at doses that had no effects on ICSS response in the absence of cocaine. Abnormalities of mood and reward are common in psychiatric disorders, and these results suggest that lacosamide deserves further study in models of these disorders.
MeSH term(s)	Acetamides/pharmacology ; Animals ; Anticonvulsants/pharmacology ; Cocaine/pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Reinforcement Schedule ; Reward ; Self Stimulation/drug effects ; Self Stimulation/physiology ; Treatment Outcome ; Triazines/pharmacology ; Valproic Acid/pharmacology
Chemical Substances	Acetamides ; Anticonvulsants ; Triazines ; lacosamide (563KS2PQY5) ; Valproic Acid (614OI1Z5WI) ; Cocaine (I5Y540LHVR) ; lamotrigine (U3H27498KS)
Language	English
Publishing date	2012-10-15
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2012.08.030
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Article ; Online: Kappa-opioid ligands in the study and treatment of mood disorders.

Carlezon, William A / Béguin, Cécile / Knoll, Allison T / Cohen, Bruce M

Pharmacology & therapeutics

2009 Volume 123, Issue 3, Page(s) 334–343

Abstract: The biological basis of mood is not understood. Most research on mood and affective states has focused on the roles of brain systems containing monoamines (e.g., dopamine, norepinephrine, serotonin). However, it is becoming clear that endogenous opioid ... ...

Abstract	The biological basis of mood is not understood. Most research on mood and affective states has focused on the roles of brain systems containing monoamines (e.g., dopamine, norepinephrine, serotonin). However, it is becoming clear that endogenous opioid systems in the brain may also be involved in the regulation of mood. In this review, we focus on the potential utility of kappa-opioid receptor (KOR) ligands in the study and treatment of psychiatric disorders. Research from our group and others suggests that KOR antagonists might be useful for depression, KOR agonists might be useful for mania, and KOR partial agonists might be useful for mood stabilization. Currently available KOR agents have some unfavorable properties that might be addressed through medicinal chemistry. The development of KOR-selective agents with improved drug-like characteristics would facilitate preclinical and clinical studies designed to evaluate the possibility that KORs are a feasible target for new medications.
MeSH term(s)	Animals ; Bipolar Disorder/drug therapy ; Bipolar Disorder/physiopathology ; Depression/drug therapy ; Depression/physiopathology ; Drug Delivery Systems ; Drug Design ; Humans ; Ligands ; Mood Disorders/drug therapy ; Mood Disorders/physiopathology ; Receptors, Opioid, kappa/agonists ; Receptors, Opioid, kappa/antagonists & inhibitors
Chemical Substances	Ligands ; Receptors, Opioid, kappa
Language	English
Publishing date	2009-06-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2009.05.008
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Differential signaling properties at the kappa opioid receptor of 12-epi-salvinorin A and its analogues

Béguin, Cécile / Potuzak, Justin / Xu, Wei / Liu-Chen, Lee-Yuan / Streicher, John M / Groer, Chad E / Bohn, Laura M / Carlezon, William A., Jr / Cohen, Bruce M

Bioorganic & medicinal chemistry letters. 2012 Jan. 15, v. 22, no. 2

2012

Abstract: The kappa opioid receptor (KOPR) has been identified as a potential drug target to prevent or alter the course of mood, anxiety and addictive disorders or reduce response to stress. In a search for highly potent and selective KOPR partial agonists as ... ...

Abstract	The kappa opioid receptor (KOPR) has been identified as a potential drug target to prevent or alter the course of mood, anxiety and addictive disorders or reduce response to stress. In a search for highly potent and selective KOPR partial agonists as pharmacological tools, we have modified 12-epi-salvinorin A, a compound which we have previously observed to be a KOPR partial agonist. Five analogues of 12-epi-salvinorin A were synthesized and their effects on G protein activation as well as β-arrestin2 recruitment were evaluated. Only 12-epi-salvinorin A (1) partially activated signaling through G proteins, yet acted as a full agonist in the β-arrestin 2 DiscoveRx assay. Other salvinorin analogues tested in these functional assays were full agonists in both assays of KOPR activation. By comparison, the non-selective opioid ligand nalbuphine, known to be a partial agonist for G-protein activation, was also a partial agonist for the β-arrestin mediated signaling pathway activated through KOPR.
Keywords	proteins ; drugs ; stress response ; signal transduction ; agonists ; anxiety
Language	English
Dates of publication	2012-0115
Size	p. 1023-1026.
Publishing place	Elsevier Ltd
Document type	Article
Note	2019-12-06
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2011.11.128
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats.

Nemeth, Christina L / Paine, Tracie A / Rittiner, Joseph E / Béguin, Cécile / Carroll, F Ivy / Roth, Bryan L / Cohen, Bruce M / Carlezon, William A

Psychopharmacology

2010 Volume 210, Issue 2, Page(s) 263–274

Abstract: Background: Disruptions in perception and cognition are characteristic of psychiatric conditions such as schizophrenia. Studies of pharmacological agents that alter perception and cognition in humans might provide a better understanding of the brain ... ...

Abstract	Background: Disruptions in perception and cognition are characteristic of psychiatric conditions such as schizophrenia. Studies of pharmacological agents that alter perception and cognition in humans might provide a better understanding of the brain substrates of these complex processes. One way to study these states in rodents is with tests that require attention and visual perception for correct performance. Methods: We examined the effects of two drugs that cause disruptions in perception and cognition in humans-the kappa-opioid receptor (KOR) agonist salvinorin A (salvA; 0.125-4.0 mg/kg) and the non-competitive NMDA receptor antagonist ketamine (0.63-20 mg/kg)-on behavior in rats using the 5-choice serial reaction time task (5CSRTT), a food-motivated test that quantifies attention. We also compared the binding profiles of salvA and ketamine at KORs and NMDA receptors. Results: SalvA and ketamine produced the same pattern of disruptive effects in the 5CSRTT, characterized by increases in signs often associated with reduced motivation (omission errors) and deficits in processing (elevated latencies to respond correctly). Sessions in which rats were fed before testing suggest that reduced motivation produces a subtly different pattern of behavior. Pretreatment with the KOR antagonist JDTic (10 mg/kg) blocked all salvA effects and some ketamine effects. Binding and function studies revealed that ketamine is a full agonist at KORs, although not as potent or selective as salvA. Conclusions: SalvA and ketamine have previously under-appreciated similarities in their behavioral effects and pharmacological profiles. By implication, KORs might be involved in some of the cognitive abnormalities observed in psychiatric disorders such as schizophrenia.
MeSH term(s)	Animals ; Attention/drug effects ; Diterpenes, Clerodane/pharmacology ; Dose-Response Relationship, Drug ; Ketamine/pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Reaction Time/drug effects ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Receptors, Opioid, kappa/agonists
Chemical Substances	Diterpenes, Clerodane ; Receptors, N-Methyl-D-Aspartate ; Receptors, Opioid, kappa ; Ketamine (690G0D6V8H) ; salvinorin A (T56W91NG6J)
Language	English
Publishing date	2010-04-01
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-010-1834-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Long-acting κ opioid antagonists nor-BNI, GNTI and JDTic

Munro Thomas A / Berry Loren M / Van’t Veer Ashlee / Béguin Cécile / Carroll F / Zhao Zhiyang / Carlezon William A / Cohen Bruce M

BMC Pharmacology, Vol 12, Iss 1, p

pharmacokinetics in mice and lipophilicity

2012 Volume 5

Abstract: Abstract Background Nor-BNI, GNTI and JDTic induce κ opioid antagonism that is delayed by hours and can persist for months. Other effects are transient. It has been proposed that these drugs may be slowly absorbed or distributed, and may dissolve in cell ...

Abstract	Abstract Background Nor-BNI, GNTI and JDTic induce κ opioid antagonism that is delayed by hours and can persist for months. Other effects are transient. It has been proposed that these drugs may be slowly absorbed or distributed, and may dissolve in cell membranes, thus slowing elimination and prolonging their effects. Recent evidence suggests, instead, that they induce prolonged desensitization of the κ opioid receptor. Methods To evaluate these hypotheses, we measured relevant physicochemical properties of nor-BNI, GNTI and JDTic, and the timecourse of brain and plasma concentrations in mice after intraperitoneal administration (using LC-MS-MS). Results In each case, plasma levels were maximal within 30 min and declined by >80% within four hours, correlating well with previously reported transient effects. A strong negative correlation was observed between plasma levels and the delayed, prolonged timecourse of κ antagonism. Brain levels of nor-BNI and JDTic peaked within 30 min, but while nor-BNI was largely eliminated within hours, JDTic declined gradually over a week. Brain uptake of GNTI was too low to measure accurately, and higher doses proved lethal. None of the drugs were highly lipophilic, showing high water solubility (> 45 mM) and low distribution into octanol (log D 7.4 < 2). Brain homogenate binding was within the range of many shorter-acting drugs (>7% unbound). JDTic showed P-gp-mediated efflux; nor- BNI and GNTI did not, but their low unbound brain uptake suggests efflux by another mechanism. Conclusions The negative plasma concentration-effect relationship we observed is difficult to reconcile with simple competitive antagonism, but is consistent with desensitization. The very slow elimination of JDTic from brain is surprising given that it undergoes active efflux, has modest affinity for homogenate, and has a shorter duration of action than nor-BNI under these conditions. We propose that this persistence may result from entrapment in cellular compartments such as lysosomes.
Keywords	Norbinaltorphimine ; Nor-BNI ; 5’-guanidinonaltrindole ; 5’-GNTI ; JDTic ; Pharmacokinetics ; Lipophilicity ; P-gp ; JNK1 ; MAPK8 ; Therapeutics. Pharmacology ; RM1-950 ; Medicine ; R ; DOAJ:Therapeutics ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Language	English
Publishing date	2012-05-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Salvinorin A and derivatives: protection from metabolism does not prolong short-term, whole-brain residence.

Hooker, Jacob M / Munro, Thomas A / Béguin, Cécile / Alexoff, David / Shea, Colleen / Xu, Youwen / Cohen, Bruce M

Neuropharmacology

2009 Volume 57, Issue 4, Page(s) 386–391

Abstract: Salvinorin A (SA) is a potent kappa opioid agonist with a brief duration of action. Consistent with this, our previous positron emission tomography (PET) studies of carbon-11 labeled SA showed that brain levels decrease rapidly after intravenous ... ...

Abstract	Salvinorin A (SA) is a potent kappa opioid agonist with a brief duration of action. Consistent with this, our previous positron emission tomography (PET) studies of carbon-11 labeled SA showed that brain levels decrease rapidly after intravenous administration. SA is rapidly metabolized, giving the much less potent salvinorin B (SB), which is presumed to be responsible in part for SA's brief duration of action. To test this, we labeled the metabolically stable methyl ester of SA and SB with carbon-11 and compared their pharmacokinetics by PET imaging after intravenous administration to baboons. Labeling of salvinorin B ethoxymethyl ether (EOM-SB), a derivative with greater potency and resistance to metabolism, provided an additional test of the role of metabolism in brain efflux. Plasma analysis confirmed that SB and EOM-SB exhibited greater metabolic stability than SA. However, the three compounds exhibited very similar pharmacokinetics in brain, entering and exiting rapidly. This suggests that metabolism is not solely responsible for the brief brain residence time of SA. We determined that whole-brain concentrations of EOM-SB declined more slowly than SA after intraperitoneal administration in rodents. This is likely due to a combination in EOM-SB's increased metabolic stability and its decreased plasma protein affinity. Our results suggest that protecting salvinorin A derivatives from metabolism will prolong duration of action, but only when administered by routes giving slow absorption.
MeSH term(s)	Animals ; Brain/diagnostic imaging ; Brain/drug effects ; Brain/metabolism ; Carbon Radioisotopes ; Central Nervous System Agents/administration & dosage ; Central Nervous System Agents/blood ; Central Nervous System Agents/pharmacokinetics ; Diterpenes/administration & dosage ; Diterpenes/blood ; Diterpenes/pharmacokinetics ; Diterpenes, Clerodane/administration & dosage ; Diterpenes, Clerodane/blood ; Diterpenes, Clerodane/pharmacokinetics ; Female ; Injections, Intraperitoneal ; Injections, Intravenous ; Kinetics ; Male ; Papio anubis ; Positron-Emission Tomography ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Carbon Radioisotopes ; Central Nervous System Agents ; Diterpenes ; Diterpenes, Clerodane ; salvinorin B ; salvinorin B ethoxymethyl ether ; salvinorin A (T56W91NG6J)
Language	English
Publishing date	2009-07-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2009.06.044
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Article ; Online: Selective κ opioid antagonists nor-BNI, GNTI and JDTic have low affinities for non-opioid receptors and transporters.

Munro, Thomas A / Huang, Xi-Ping / Inglese, Carmela / Perrone, Maria Grazia / Van't Veer, Ashlee / Carroll, F Ivy / Béguin, Cécile / Carlezon, William A / Colabufo, Nicola A / Cohen, Bruce M / Roth, Bryan L

PloS one

2013 Volume 8, Issue 8, Page(s) e70701

Abstract: Background: Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them ...

Abstract	Background: Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets. Results: In binding assays, the three antagonists showed no detectable affinity (K(i)≥10 µM) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity. All three compounds showed low nanomolar affinity for κ opioid receptors, with moderate selectivity over μ and δ (3 to 44-fold). Nor-BNI bound weakly to the α(2C)-adrenoceptor (K(i) = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the α(1A)-adrenoceptor (EC₅₀ = 41 nM), but did not activate the receptor, displace radioligands, or enhance PI hydrolysis. This suggests that it is a functionally-selective allosteric enhancer. GNTI was also a weak M₁ receptor antagonist (K(B) = 3.7 µM). JDTic bound to the noradrenaline transporter (K(i) = 54 nM), but only weakly inhibited transport (IC₅₀ = 1.1 µM). JDTic also bound to the opioid-like receptor NOP (K(i) = 12 nM), but gave little antagonism even at 30 µM. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers. Conclusions: Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of α(1A)-adrenoceptors). This may contribute to GNTI's severe transient effects. Plasma concentrations of nor-BNI and GNTI may be high enough to affect some peripheral non-opioid targets. Nonetheless, κ opioid antagonism persists for weeks or months after these transient effects dissipate. With an adequate pre-administration interval, our results therefore strengthen the evidence that nor-BNI, GNTI and JDTic are highly selective κ opioid antagonists.
MeSH term(s)	Allosteric Regulation ; Biological Transport ; Caco-2 Cells ; Calcium/metabolism ; Guanidines/metabolism ; Guanidines/pharmacology ; Humans ; Kinetics ; Morphinans/metabolism ; Morphinans/pharmacology ; Naltrexone/analogs & derivatives ; Naltrexone/metabolism ; Naltrexone/pharmacology ; Narcotic Antagonists/metabolism ; Narcotic Antagonists/pharmacology ; Norepinephrine/metabolism ; Norepinephrine Plasma Membrane Transport Proteins/metabolism ; Piperidines/metabolism ; Piperidines/pharmacology ; Protein Binding ; Receptors, Adrenergic, alpha/metabolism ; Receptors, Opioid, delta/metabolism ; Receptors, Opioid, kappa/antagonists & inhibitors ; Receptors, Opioid, kappa/metabolism ; Receptors, Opioid, mu/metabolism ; Tetrahydroisoquinolines/metabolism ; Tetrahydroisoquinolines/pharmacology
Chemical Substances	17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan ; 7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide ; Guanidines ; Morphinans ; Narcotic Antagonists ; Norepinephrine Plasma Membrane Transport Proteins ; Piperidines ; Receptors, Adrenergic, alpha ; Receptors, Opioid, delta ; Receptors, Opioid, kappa ; Receptors, Opioid, mu ; Tetrahydroisoquinolines ; norbinaltorphimine (36OOQ86QM1) ; Naltrexone (5S6W795CQM) ; Calcium (SY7Q814VUP) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2013-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0070701
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Article: N-Substituted amino acid N'-benzylamides: synthesis, anticonvulsant, and metabolic activities.

Béguin, Cécile / LeTiran, Arnaud / Stables, James P / Voyksner, Robert D / Kohn, Harold

Bioorganic & medicinal chemistry

2004 Volume 12, Issue 11, Page(s) 3079–3096

Abstract: Amino acid amides (AAA) were prepared and evaluated in seizure models. The AAA displayed moderate-to-excellent activity in the maximal electroshock seizure (MES) test and were devoid of activity in the subcutaneous Metrazol-induced (scMet) seizure test. ... ...

Abstract	Amino acid amides (AAA) were prepared and evaluated in seizure models. The AAA displayed moderate-to-excellent activity in the maximal electroshock seizure (MES) test and were devoid of activity in the subcutaneous Metrazol-induced (scMet) seizure test. The AAA anticonvulsant activity was neither strongly influenced by the C(2) substituent nor by the degree of terminal amine substitution. An in vitro metabolism study suggested that the structure-activity relationship pattern was due, in part, to metabolic processes that occurred at the N-terminal amine unit.
MeSH term(s)	Amides/chemical synthesis ; Amides/chemistry ; Amides/pharmacology ; Amino Acids/chemical synthesis ; Amino Acids/chemistry ; Amino Acids/metabolism ; Animals ; Anticonvulsants/chemical synthesis ; Anticonvulsants/metabolism ; Anticonvulsants/pharmacology ; Benzyl Compounds/chemical synthesis ; Benzyl Compounds/chemistry ; Benzyl Compounds/pharmacology ; Rats ; Stereoisomerism ; Structure-Activity Relationship
Chemical Substances	Amides ; Amino Acids ; Anticonvulsants ; Benzyl Compounds
Language	English
Publishing date	2004-06-01
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2004.02.043
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Article: Application of predictive QSAR models to database mining: identification and experimental validation of novel anticonvulsant compounds.

Shen, Min / Béguin, Cécile / Golbraikh, Alexander / Stables, James P / Kohn, Harold / Tropsha, Alexander

Journal of medicinal chemistry

2004 Volume 47, Issue 9, Page(s) 2356–2364

Abstract: We have developed a drug discovery strategy that employs variable selection quantitative structure-activity relationship (QSAR) models for chemical database mining. The approach starts with the development of rigorously validated QSAR models obtained ... ...

Abstract	We have developed a drug discovery strategy that employs variable selection quantitative structure-activity relationship (QSAR) models for chemical database mining. The approach starts with the development of rigorously validated QSAR models obtained with the variable selection k nearest neighbor (kNN) method (or, in principle, with any other robust model-building technique). Model validation is based on several statistical criteria, including the randomization of the target property (Y-randomization), independent assessment of the training set model's predictive power using external test sets, and the establishment of the model's applicability domain. All successful models are employed in database mining concurrently; in each case, only variables selected as a result of model building (termed descriptor pharmacophore) are used in chemical similarity searches comparing active compounds of the training set (queries) with those in chemical databases. Specific biological activity (characteristic of the training set compounds) of external database entries found to be within a predefined similarity threshold of the training set molecules is predicted on the basis of the validated QSAR models using the applicability domain criteria. Compounds judged to have high predicted activities by all or the majority of all models are considered as consensus hits. We report on the application of this computational strategy for the first time for the discovery of anticonvulsant agents in the Maybridge and National Cancer Institute (NCI) databases containing ca. 250,000 compounds combined. Forty-eight anticonvulsant agents of the functionalized amino acid (FAA) series were used to build kNN variable selection QSAR models. The 10 best models were applied to mining chemical databases, and 22 compounds were selected as consensus hits. Nine compounds were synthesized and tested at the NIH Epilepsy Branch, Rockville, MD using the same biological test that was employed to assess the anticonvulsant activity of the training set compounds; of these nine, four were exact database hits and five were derived from the hits by minor chemical modifications. Seven of these nine compounds were confirmed to be active, indicating an exceptionally high hit rate. The approach described in this report can be used as a general rational drug discovery tool.
MeSH term(s)	Amides/chemistry ; Amides/pharmacology ; Animals ; Anticonvulsants/chemistry ; Anticonvulsants/pharmacology ; Databases, Factual ; Mice ; Quantitative Structure-Activity Relationship ; Stereoisomerism
Chemical Substances	Amides ; Anticonvulsants
Language	English
Publishing date	2004-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm030584q
Database	MEDical Literature Analysis and Retrieval System OnLINE

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