The Experts below are selected from a list of 4614 Experts worldwide ranked by ideXlab platform
Takashi Sugane - One of the best experts on this subject based on the ideXlab platform.
-
atropisomeric 4 phenyl 4h 1 2 4 triazoles as selective Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2013Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Shuichi Sakamoto, Shinichi TsukamotoAbstract:We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as Glycine Transporter 1 (GlyT1) inhibitors. Structure–activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
-
synthesis and biological evaluation of 4h 1 2 4 triazol 4 yl isoquinoline derivatives as selective Glycine Transporter 1 inhibitors
Bioorganic & Medicinal Chemistry, 2012Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Takuma Morita, Shuichi SakamotoAbstract:Abstract To identify novel Glycine Transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure–activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
-
synthesis and biological evaluation of 3 biphenyl 4 yl 4 phenyl 4h 1 2 4 triazoles as novel Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2011Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Atsuyuki Kohara, Takuma MoritaAbstract:We describe the preparation and evaluation of a novel series of Glycine Transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.
Benjamin K Yee - One of the best experts on this subject based on the ideXlab platform.
-
inhibition of Glycine Transporter 1 the yellow brick road to new schizophrenia therapy
Current Pharmaceutical Design, 2015Co-Authors: Philipp Singer, Sylvain Dubroqua, Benjamin K YeeAbstract:While pharmacological blockade of dopamine D2 receptor can effectively suppress the psychotic or positive symptoms of schizophrenia, there is no satisfactory medication for the negative and cognitive symptoms of schizophrenia in spite of the proliferation of second generation antipsychotic drugs. Excitements over a new class of third generation antipsychotics that might possibly fill this urgent medical need have been prompted by the recent development of Glycine Transporter 1 (GlyT1) inhibitors. The impetus of this novel pharmacological strategy stems directly from the prevailing hypothesis that negative and cognitive symptoms are attributable to the hypofunction of glutamatergic signalling via the N-methyl-D-aspartate (NMDA) receptor in the brain. Inhibition of GlyT1 reduces clearance of extra-cellular Glycine near NMDA receptor-containing synapses, and thereby increases baseline occupancy of the Glycine-B site at the NR1 subunit of the NMDA receptor, which is a prerequisite of channel activation upon stimulation by the excitatory neurotransmitter glutamate. Pharmacological inhibition of GlyT1 is expected to boost NMDA receptor function and therefore alleviate persistent negative and cognitive symptoms without excessive risk of excitotoxicity associated with direct NMDA receptor agonists. The recently completed phase III clinical trials of the Roche compound, bitopertin (a.k.a. RG1678 or RO-4917838) had initially raised hope that this new class of drugs might represent the first successful translation of the glutamate hypothesis of schizophrenia to the clinic. However, the outcomes of the multi-centre bitopertin clinical trials have been disappointing. The present review seeks to examine this promise through a critical survey of the latest clinical and preclinical findings on the therapeutic potential of GlyT1 inhibition or down-regulation.
-
deletion of forebrain Glycine Transporter 1 enhances conditioned freezing to a reliable but not an ambiguous cue for threat in a conditioned freezing paradigm
Behavioural Brain Research, 2014Co-Authors: Sylvain Dubroqua, Philipp Singer, Benjamin K YeeAbstract:Abstract Enhanced expression of Pavlovian aversive conditioning but not appetitive conditioning may indicate a bias in the processing of threatening or fearful events. Mice with disruption of Glycine Transporter 1 (GlyT1) in forebrain neurons exhibit such a bias, but they are at the same time highly sensitive to manipulations that hinder the development of the conditioned response (CR) suggesting that the mutation may modify higher cognitive processes that extract predictive information between environmental cues. Here, we further investigated the development of fear conditioning in forebrain neuronal GlyT1 knockout mice when the predictiveness of a tone stimulus for foot-shock was rendered ambiguous by interspersing [tone → no shock] trials in-between [tone → shock] trials during acquisition. The CR to the ambiguous tone CS (conditioned stimulus) was compared with that generated by an unambiguous CS that was always followed by the shock US (unconditioned stimulus) during acquisition. We showed that rendering the CS ambiguous as described significantly attenuated the CR in the mutants, but it was not sufficient to modify the CR in the control mice. It is concluded that disruption of GlyT1 in forebrain neurons does not increase the risk of forming spurious and potentially maladaptive fear associations.
-
forebrain Glycine Transporter 1 deletion enhances sensitivity to cs us discontiguity in classical conditioning
Neurobiology of Learning and Memory, 2014Co-Authors: Philipp Singer, Sylvain Dubroqua, Benjamin K YeeAbstract:The deletion of Glycine Transporter 1 (GlyT1) in forebrain neurons can apparently strengthen Pavlovian aversive conditioning, but this phenotype is not expressed if conditioning followed non-reinforced pre-exposures of the to-be-conditioned stimulus (CS). To examine whether GlyT1 disruption may only enhance aversive associative learning under conditions that most favour the formation of CS-US excitatory link, we evaluated the impact of GlyT1 disruption on the trace conditioning procedure whereby a trace interval between a tone CS and a shock US was introduced during conditioning. CS and US occurrences were thus rendered discontiguous, which was expected to impede conditioning compared with contiguous CS-US pairing. Conditioned freezing to the CS was measured in a retention test conducted 48 h after conditioning. The genetic disruption significantly modified the temporal dynamics of the freezing response over the course of the 8-min presentation of the CS, although the immediate conditioned response to the CS was unaffected. The separation between "trace" and "no-trace" conditions was augmented in the mutant mice, but this only became apparent in mid-session; and the augmentation can be attributed to the combined effects of (i) weaker conditioned freezing in the mutant relative to control subjects in the "trace" condition, and (ii) stronger conditioned freezing in mutants relative controls in the "no-trace" condition. The demonstrated increased sensitivity to the effect of CS-US temporal discontiguity further highlights the importance of GlyT1-dependent mechanisms in the regulation of associative learning.
-
examining the sex and circadian dependency of a learning phenotype in mice with Glycine Transporter 1 deletion in two pavlovian conditioning paradigms
Neurobiology of Learning and Memory, 2011Co-Authors: Sylvain Dubroqua, Detlev Boison, Hanns Mohler, Joram Feldon, Benjamin K YeeAbstract:Behavioural characterisation of transgenic mice has been instrumental in search of therapeutic targets for the modulation of cognitive function. However, little effort has been devoted to phenotypic characterisation across environmental conditions and genomic differences such as sex and strain, which is essential to translational research. The present study is an effort in this direction. It scrutinised the stability and robustness of the phenotype of enhanced Pavlovian conditioning reported in mice with forebrain neuronal deletion of Glycine Transporter 1 by evaluating the possible presence of sex and circadian dependency, and its consistency across aversive and appetitive conditioning paradigms. The Pavlovian phenotype was essentially unaffected by the time of testing between the two circadian phases, but it was modified by sex in both conditioning paradigms. We observed that the effect size of the phenotype was strongest in female mice tested during the dark phase in the aversive paradigm. Critically, the presence of the phenotype in female mutants was accompanied by an increase in resistance to extinction. Similarly, enhanced conditioned responding once again emerged solely in female mutants in the appetitive conditioning experiment, which was again associated with an increased resistance to extinction across days, but male mutants exhibited an opposite trend towards facilitation of extinction. The present study has thus added hitherto unknown qualifications and specifications of a previously reported memory enhancing phenotype in this mouse line by identifying the determinants of the magnitude and direction of the expressed phenotype. This in-depth comparative approach is of value to the interpretation of behavioural findings in general.
-
modulation of sensorimotor gating in prepulse inhibition by conditional brain Glycine Transporter 1 deletion in mice
European Neuropsychopharmacology, 2011Co-Authors: Philipp Singer, Detlev Boison, Hanns Mohler, Joram Feldon, Benjamin K YeeAbstract:Inhibition of Glycine Transporter 1 (GlyT1) augments N-methyl-D-aspartate receptor (NMDAR)-mediated transmission and represents a potential antipsychotic drug target according to the NMDAR hypofunction hypothesis of schizophrenia. Preclinical evaluation of GlyT1 inhibiting drugs using the prepulse inhibition (PPI) test, however, has yielded mixed outcomes. Here, we tested for the first time the impact of two conditional knockouts of GlyT1 on PPI expression. Complete deletion of GlyT1 in the cerebral cortices confers resistance to PPI disruption induced by the NMDAR blocker MK-801 (0.2mg/kg, i.p.) without affecting PPI expression in unchallenged conditions. In contrast, restricting GlyT1 deletion to neurons in forebrain including the striatum significantly attenuated PPI, and the animals remained sensitive to the PPI-disruptive effect of MK-801 at the same dose. These results demonstrate in mice that depending on the regional and/or cell-type specificity, deletion of the GlyT1 gene could yield divergent effects on PPI.
Takeshi Fuchigami - One of the best experts on this subject based on the ideXlab platform.
-
synthesis and evaluation of 2 chloro n s s 1 11 c methylpiperidin 2 yl phenyl methyl 3 trifluoromethyl benzamide 11 c n methyl ssr504734 as a pet radioligand for Glycine Transporter 1
EJNMMI research, 2012Co-Authors: Takeshi Fuchigami, Yasuhiro Magata, Akihiro Takano, Balazs Gulyas, Zhisheng Jia, Sjoerd J Finnema, Jan Andersson, Ryuji Nakao, Mamoru HaratakeAbstract:Dysfunction of the Glycine Transporter 1 (GlyT1) has been suggested to be involved in psychiatric disorders such as schizophrenia. GlyT1 inhibitors have therefore been considered to have antipsychotic therapeutic potential. Positron emission tomography (PET) imaging probes for GlyT1 are, consequently, expected to be useful for investigating the mechanism of such disease conditions and for measuring occupancy of GlyT1 inhibitors in vivo. The aim of this study was to assess the potential of 2-chloro N-[(S)-{(S)-1-[11 C]methylpiperidin-2-yl} (phenyl)methyl] 3-trifluoromethyl-benzamide ([11 C]N-methyl-SSR504734) as a PET imaging agent for GlyT1. [11 C]N-methyl-SSR504734 was synthesized by N-[11 C]methylation of SSR504734 via [11 C]CH3OTf. In vitro brain distribution of [11 C]N-methyl-SSR504734 was tested in whole-hemisphere autoradiography (ARG) on human brain slices. Initial PET studies were performed using a cynomolgus monkey at baseline and after pretreatment with 0.1 to 1.5 mg/kg of SSR504734. Then, PET studies using rhesus monkeys were performed with arterial blood sampling at baseline and after pretreatment with 1.5 to 4.5 mg/kg SSR504734. Distribution volumes (V T) were calculated with a two-tissue compartment model, and GlyT1 occupancy by SSR504734 was estimated using a Lassen plot approach. [11 C]N-methyl-SSR504734 was successfully synthesized in moderate radiochemical yield and high specific radioactivity. In the ARG experiments, [11 C]N-methyl-SSR504734 showed specific binding in the white matter and pons. In the initial PET experiments in a cynomolgus monkey, [11 C]N-methyl-SSR504734 showed high brain uptake and consistent distribution with previously reported GlyT1 expression in vivo (thalamus, brainstem > cerebellum > cortical regions). However, the brain uptake increased after pretreatment with SSR504734. Further PET studies in rhesus monkeys showed a similar increase of brain uptake after pretreatment with SSR504734. However, the V T of [11 C]N-methyl-SSR504734 was found to decrease after pretreatment of SSR504734 in a dose-dependent manner. GlyT1 occupancy was calculated to be 45% and 73% at 1.5 and 4.5 mg/kg of SSR504734, respectively. [11 C]N-methyl-SSR504734 is demonstrated to be a promising PET radioligand for GlyT1 in nonhuman primates. The present results warrant further PET studies in human subjects.
-
synthesis and characterization of 125 i 2 iodo n s s 1 methylpiperidin 2 yl phenyl methyl 3 trifluoromethyl benzamide as novel imaging probe for Glycine Transporter 1
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Takeshi Fuchigami, Mamoru Haratake, Yasuhiro Magata, Terushi Haradahira, Morio NakayamaAbstract:In this study, 2-iodo substituted 1-methylpiperidin-2-yl benzamide derivatives were synthesized and evaluated as candidate SPECT imaging agents for Glycine Transporter 1 (GlyT1). In JAR cells, which predominantly express GlyT1, 2-iodo N-[(S)-{(S)-1-methylpiperidin-2-yl}(phenyl)methyl]3-trifluoromethyl-benzamide (5) showed excellent inhibitory activity of [(3)H]Glycine uptake (IC(50)=2.4 nM). Saturation assay in rat cortical membranes revealed that [(125)I]5 had a single high affinity binding site with a K(d) of 1.54 nM and a B(max) of 3.40 pmol/mg protein. In vitro autoradiography demonstrated that [(125)I]5 showed consistent accumulation with GlyT1 expression. The in vitro binding was greatly inhibited by GlyT1 inhibitors but not by other site ligands, which suggested the high specific binding of [(125)I]5 with GlyT1. In the biodistribution and ex vivo autoradiography studies using mice, [(125)I]5 showed high blood-brain barrier permeability (1.68-2.17% dose/g at 15-60 min) and similar regional brain distribution pattern with in vitro results. In addition, pre-treatment of GlyT1 ligands resulted in significant decrease of [(125)I]5 binding in the GlyT1-rich regions. This preliminary study demonstrated that radio-iodinated 5 is a promising SPECT imaging probe for GlyT1.
Takeshi Suzuki - One of the best experts on this subject based on the ideXlab platform.
-
atropisomeric 4 phenyl 4h 1 2 4 triazoles as selective Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2013Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Shuichi Sakamoto, Shinichi TsukamotoAbstract:We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as Glycine Transporter 1 (GlyT1) inhibitors. Structure–activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
-
synthesis and biological evaluation of 4h 1 2 4 triazol 4 yl isoquinoline derivatives as selective Glycine Transporter 1 inhibitors
Bioorganic & Medicinal Chemistry, 2012Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Takuma Morita, Shuichi SakamotoAbstract:Abstract To identify novel Glycine Transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure–activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
-
synthesis and biological evaluation of 3 biphenyl 4 yl 4 phenyl 4h 1 2 4 triazoles as novel Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2011Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Atsuyuki Kohara, Takuma MoritaAbstract:We describe the preparation and evaluation of a novel series of Glycine Transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.
Takahiko Tobe - One of the best experts on this subject based on the ideXlab platform.
-
atropisomeric 4 phenyl 4h 1 2 4 triazoles as selective Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2013Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Shuichi Sakamoto, Shinichi TsukamotoAbstract:We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as Glycine Transporter 1 (GlyT1) inhibitors. Structure–activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
-
synthesis and biological evaluation of 4h 1 2 4 triazol 4 yl isoquinoline derivatives as selective Glycine Transporter 1 inhibitors
Bioorganic & Medicinal Chemistry, 2012Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Takuma Morita, Shuichi SakamotoAbstract:Abstract To identify novel Glycine Transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure–activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
-
synthesis and biological evaluation of 3 biphenyl 4 yl 4 phenyl 4h 1 2 4 triazoles as novel Glycine Transporter 1 inhibitors
Journal of Medicinal Chemistry, 2011Co-Authors: Takashi Sugane, Takahiko Tobe, Wataru Hamaguchi, Itsuro Shimada, Kyoichi Maeno, Junji Miyata, Takeshi Suzuki, Tetsuya Kimizuka, Atsuyuki Kohara, Takuma MoritaAbstract:We describe the preparation and evaluation of a novel series of Glycine Transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.