|
Compound was tested for the binding affinity against 5-hydroxytryptamine 1A receptor by using [3H]DPAT as radioligand
|
None
|
238.0
nM
|
|
Journal : J. Med. Chem.
Title : Separation of alpha 1 adrenergic and N-methyl-D-aspartate antagonist activity in a series of ifenprodil compounds.
Year : 1991
Volume : 34
Issue : 10
First Page : 3085
Last Page : 3090
Authors : Chenard BL, Shalaby IA, Koe BK, Ronau RT, Butler TW, Prochniak MA, Schmidt AW, Fox CB.
Abstract : Ifenprodil (1) represents a new class of N-methyl-D-aspartate (NMDA) antagonist. This drug also possesses potent activity at several other brain receptors (most notably alpha 1 adrenergic receptors). We have prepared the enantiomers and diastereomers of ifenprodil along with a series of partial structures in order to explore the basic structure activity relations within this class of compounds. From this study, it is clear that alpha 1 adrenergic and NMDA receptor activities may be separated by selection of the threo relative stereochemistry. Examination of the optical isomers of threo-ifenprodil (2) reveals that no further improvement in receptor selectivity is gained from either antipode. Individual removal of most of the structural fragments from the ifenprodil molecule generally results in less active compounds although fluorinated derivative 9 with threo relative stereochemistry is somewhat more potent and substantially more selective for the NMDA receptor. Finally a minimum structure for activity in this series (14) has been identified. This stripped-down version of ifenprodil possesses nearly equivalent affinity for the NMDA receptor with no selectivity over alpha 1 adrenergic receptors.
|
Compound was tested for the binding affinity against 5-hydroxytryptamine 2 receptor by using [3H]ketanserin as radioligand
|
None
|
610.0
nM
|
|
Journal : J. Med. Chem.
Title : Separation of alpha 1 adrenergic and N-methyl-D-aspartate antagonist activity in a series of ifenprodil compounds.
Year : 1991
Volume : 34
Issue : 10
First Page : 3085
Last Page : 3090
Authors : Chenard BL, Shalaby IA, Koe BK, Ronau RT, Butler TW, Prochniak MA, Schmidt AW, Fox CB.
Abstract : Ifenprodil (1) represents a new class of N-methyl-D-aspartate (NMDA) antagonist. This drug also possesses potent activity at several other brain receptors (most notably alpha 1 adrenergic receptors). We have prepared the enantiomers and diastereomers of ifenprodil along with a series of partial structures in order to explore the basic structure activity relations within this class of compounds. From this study, it is clear that alpha 1 adrenergic and NMDA receptor activities may be separated by selection of the threo relative stereochemistry. Examination of the optical isomers of threo-ifenprodil (2) reveals that no further improvement in receptor selectivity is gained from either antipode. Individual removal of most of the structural fragments from the ifenprodil molecule generally results in less active compounds although fluorinated derivative 9 with threo relative stereochemistry is somewhat more potent and substantially more selective for the NMDA receptor. Finally a minimum structure for activity in this series (14) has been identified. This stripped-down version of ifenprodil possesses nearly equivalent affinity for the NMDA receptor with no selectivity over alpha 1 adrenergic receptors.
|
Compound was tested for the binding affinity against Alpha-1 adrenergic receptor by using [3H]prazosin as radioligand
|
None
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Separation of alpha 1 adrenergic and N-methyl-D-aspartate antagonist activity in a series of ifenprodil compounds.
Year : 1991
Volume : 34
Issue : 10
First Page : 3085
Last Page : 3090
Authors : Chenard BL, Shalaby IA, Koe BK, Ronau RT, Butler TW, Prochniak MA, Schmidt AW, Fox CB.
Abstract : Ifenprodil (1) represents a new class of N-methyl-D-aspartate (NMDA) antagonist. This drug also possesses potent activity at several other brain receptors (most notably alpha 1 adrenergic receptors). We have prepared the enantiomers and diastereomers of ifenprodil along with a series of partial structures in order to explore the basic structure activity relations within this class of compounds. From this study, it is clear that alpha 1 adrenergic and NMDA receptor activities may be separated by selection of the threo relative stereochemistry. Examination of the optical isomers of threo-ifenprodil (2) reveals that no further improvement in receptor selectivity is gained from either antipode. Individual removal of most of the structural fragments from the ifenprodil molecule generally results in less active compounds although fluorinated derivative 9 with threo relative stereochemistry is somewhat more potent and substantially more selective for the NMDA receptor. Finally a minimum structure for activity in this series (14) has been identified. This stripped-down version of ifenprodil possesses nearly equivalent affinity for the NMDA receptor with no selectivity over alpha 1 adrenergic receptors.
|
Compound was tested for the binding affinity against Alpha-1 adrenergic receptor
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Separation of alpha 1 adrenergic and N-methyl-D-aspartate antagonist activity in a series of ifenprodil compounds.
Year : 1991
Volume : 34
Issue : 10
First Page : 3085
Last Page : 3090
Authors : Chenard BL, Shalaby IA, Koe BK, Ronau RT, Butler TW, Prochniak MA, Schmidt AW, Fox CB.
Abstract : Ifenprodil (1) represents a new class of N-methyl-D-aspartate (NMDA) antagonist. This drug also possesses potent activity at several other brain receptors (most notably alpha 1 adrenergic receptors). We have prepared the enantiomers and diastereomers of ifenprodil along with a series of partial structures in order to explore the basic structure activity relations within this class of compounds. From this study, it is clear that alpha 1 adrenergic and NMDA receptor activities may be separated by selection of the threo relative stereochemistry. Examination of the optical isomers of threo-ifenprodil (2) reveals that no further improvement in receptor selectivity is gained from either antipode. Individual removal of most of the structural fragments from the ifenprodil molecule generally results in less active compounds although fluorinated derivative 9 with threo relative stereochemistry is somewhat more potent and substantially more selective for the NMDA receptor. Finally a minimum structure for activity in this series (14) has been identified. This stripped-down version of ifenprodil possesses nearly equivalent affinity for the NMDA receptor with no selectivity over alpha 1 adrenergic receptors.
|
N-methyl-D-aspartate glutamate receptor antagonistic activity in cell culture(CC)model
|
None
|
263.0
nM
|
|
Journal : J. Med. Chem.
Title : Separation of alpha 1 adrenergic and N-methyl-D-aspartate antagonist activity in a series of ifenprodil compounds.
Year : 1991
Volume : 34
Issue : 10
First Page : 3085
Last Page : 3090
Authors : Chenard BL, Shalaby IA, Koe BK, Ronau RT, Butler TW, Prochniak MA, Schmidt AW, Fox CB.
Abstract : Ifenprodil (1) represents a new class of N-methyl-D-aspartate (NMDA) antagonist. This drug also possesses potent activity at several other brain receptors (most notably alpha 1 adrenergic receptors). We have prepared the enantiomers and diastereomers of ifenprodil along with a series of partial structures in order to explore the basic structure activity relations within this class of compounds. From this study, it is clear that alpha 1 adrenergic and NMDA receptor activities may be separated by selection of the threo relative stereochemistry. Examination of the optical isomers of threo-ifenprodil (2) reveals that no further improvement in receptor selectivity is gained from either antipode. Individual removal of most of the structural fragments from the ifenprodil molecule generally results in less active compounds although fluorinated derivative 9 with threo relative stereochemistry is somewhat more potent and substantially more selective for the NMDA receptor. Finally a minimum structure for activity in this series (14) has been identified. This stripped-down version of ifenprodil possesses nearly equivalent affinity for the NMDA receptor with no selectivity over alpha 1 adrenergic receptors.
|
Inhibition of [3H]- ifenprodil binding against Sigma opioid receptor type 2 from rat brain
|
Rattus norvegicus
|
4.9
nM
|
|
Journal : J. Med. Chem.
Title : A series of 6- and 7-piperazinyl- and -piperidinylmethylbenzoxazinones with dopamine D4 antagonist activity: discovery of a potential atypical antipsychotic agent.
Year : 1999
Volume : 42
Issue : 25
First Page : 5181
Last Page : 5187
Authors : Belliotti TR, Wustrow DJ, Brink WA, Zoski KT, Shih YH, Whetzel SZ, Georgic LM, Corbin AE, Akunne HC, Heffner TG, Pugsley TA, Wise LD.
Abstract : As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure-activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series. One of the most potent and selective compounds (26) was found to have potent activity in animal tests predictive of antipsychotic activity in humans after oral administration. This paper describes the SAR of the benzoxazinone series and the preclinical characterization of 26.
|
Inhibition of [3H]-emopamil binding to Sterol delta 8-delta 7 isomerase in guinea pig liver membrane
|
Cavia porcellus
|
2.71
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of chiral 1-[omega-(4-chlorophenoxy)alkyl]-4-methylpiperidines and their biological evaluation at sigma1, sigma2, and sterol delta8-delta7 isomerase sites.
Year : 2003
Volume : 46
Issue : 11
First Page : 2117
Last Page : 2124
Authors : Berardi F, Loiodice F, Fracchiolla G, Colabufo NA, Perrone R, Tortorella V.
Abstract : Sumitomo's patented sigma ligand 1-[3-(4-chlorophenoxy)propyl]-4-methylpiperidine (15), which has been claimed as agent for CNS disorders and neuropathies, and its lower homologue 12 were prepared along with related chiral (4-chlorophenoxy)alkylpiperidines. They were tested at sigma1, sigma2, and sterol Delta8-Delta7 isomerase (SI) sites by in vitro radioligand binding assays, to evaluate the influence of a chiral center in the alkyl chain on the selective sigma(1) binding relative to other sigma family sites. Generally high sigma1-site affinities were found, so that the chirality introduced by a methyl substitution resulted in slight differences. Nevertheless, the shorter oxyethylenic chain was beneficial to increase sigma1 selectivity. However, the (-)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine ((-)-(S)-17) reached the highest sigma1 affinity (K(i) = 0.34 nM) and the best selectivity relative to the sigma2 site (547-fold). Compound (-)-(S)-17 displayed also a moderate selectivity (11-fold) relative to the SI site.
|
Compound was tested for the binding affinity against sigma receptor by using [3H]-+3PPP as radioligand
|
None
|
3.9
nM
|
|
Journal : J. Med. Chem.
Title : Separation of alpha 1 adrenergic and N-methyl-D-aspartate antagonist activity in a series of ifenprodil compounds.
Year : 1991
Volume : 34
Issue : 10
First Page : 3085
Last Page : 3090
Authors : Chenard BL, Shalaby IA, Koe BK, Ronau RT, Butler TW, Prochniak MA, Schmidt AW, Fox CB.
Abstract : Ifenprodil (1) represents a new class of N-methyl-D-aspartate (NMDA) antagonist. This drug also possesses potent activity at several other brain receptors (most notably alpha 1 adrenergic receptors). We have prepared the enantiomers and diastereomers of ifenprodil along with a series of partial structures in order to explore the basic structure activity relations within this class of compounds. From this study, it is clear that alpha 1 adrenergic and NMDA receptor activities may be separated by selection of the threo relative stereochemistry. Examination of the optical isomers of threo-ifenprodil (2) reveals that no further improvement in receptor selectivity is gained from either antipode. Individual removal of most of the structural fragments from the ifenprodil molecule generally results in less active compounds although fluorinated derivative 9 with threo relative stereochemistry is somewhat more potent and substantially more selective for the NMDA receptor. Finally a minimum structure for activity in this series (14) has been identified. This stripped-down version of ifenprodil possesses nearly equivalent affinity for the NMDA receptor with no selectivity over alpha 1 adrenergic receptors.
|
Displacement of [3H](+/-)-emopamil from delta8-delta7 sterol isomerase (SI) site in guinea pig liver membranes
|
Cavia porcellus
|
4.7
nM
|
|
Journal : J. Med. Chem.
Title : Methyl substitution on the piperidine ring of N-[omega-(6-methoxynaphthalen-1-yl)alkyl] derivatives as a probe for selective binding and activity at the sigma(1) receptor.
Year : 2005
Volume : 48
Issue : 26
First Page : 8237
Last Page : 8244
Authors : Berardi F, Ferorelli S, Abate C, Pedone MP, Colabufo NA, Contino M, Perrone R.
Abstract : The N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl and N-(6-methoxynaphthalen-1-yl)propyl derivatives as well as their upper homologous butyl derivatives of various methylpiperidines were prepared. The piperidine moiety bearing monomethyl or geminal dimethyl groups was employed as a probe to explore sigma-subtype affinities and selectivities by radioligand binding assays at sigma(1) and sigma(2) receptors and the Delta(8)-Delta(7) sterol isomerase (SI) site. 4-Methyl derivative 31 was the most potent sigma(1) ligand (K(i)=0.030 nM) with a good selectivity profile (597-fold and 268-fold relative to sigma(2) receptor and SI site, respectively), whereas 3,3-dimethyl derivative 26 (K(i)=0.35 nM) was the most selective (680-fold) relative to the sigma(2) receptor. Both compounds can be proposed as tools for PET experiments. Furthermore, the naphthalene compounds 26, 28, 31, and 33 demonstrated antiproliferative activity in rat C6 glioma cells (EC(50) = 15.0 microM for 33), revealing a putative sigma(1) antagonist activity and opening a useful perspective in tumor research and therapy.
|
Displacement of [3H]emopamil from Delta-(8)-Delta-(7) sterol isomerase in guinea pig liver membrane
|
Cavia porcellus
|
19.8
nM
|
|
Journal : J. Med. Chem.
Title : Design and evaluation of naphthol- and carbazole-containing fluorescent sigma ligands as potential probes for receptor binding studies.
Year : 2007
Volume : 50
Issue : 19
First Page : 4648
Last Page : 4655
Authors : Ferorelli S, Abate C, Colabufo NA, Niso M, Inglese C, Berardi F, Perrone R.
Abstract : Some 3,3-dimethyl-1-(3-naphthylpropyl)piperidine and 1-cyclohexyl-4-(3-naphthylpropyl)piperazine derivatives, structurally containing naphthol as a fluorescent moiety, were prepared for being potentially used as fluorescent sigma ligands. Structurally related analogs were also prepared, where the naphthalene nucleus was replaced by the fluorescent carbazole moiety and chain length was varied. For all compounds the in vitro affinities toward sigma receptors and Delta8-Delta7 sterol isomerase site were measured, and the fluorescent properties were determined. Compound 19 gave the best results both for sigma receptor affinities (sigma1, Ki = 6.78 nM and sigma2, Ki = 26.4 nM) and fluorescence features; thus, it was chosen for in vitro saturation binding analysis at sigma receptors. The good results obtained in such assay suggested that the fluorescent compound 19 could be used instead of a radioligand in "green" binding assays.
|
Displacement of [3H]ifenprodil from rat brain membrane NR2B receptor
|
Rattus norvegicus
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Reactive derivatives for affinity labeling in the ifenprodil site of NMDA receptors.
Year : 2008
Volume : 18
Issue : 9
First Page : 2765
Last Page : 2770
Authors : Alarcon K, Martz A, Mony L, Neyton J, Paoletti P, Goeldner M, Foucaud B.
Abstract : To prepare thiol-reactive ifenprodil derivatives designed as potential probes for cysteine-substituted NR2B containing NMDA receptors, electrophilic centers were introduced in different areas of the ifenprodil structure. Intermediates and final compounds were evaluated by binding studies and by electrophysiology to determine the structural requirements for their selectivity. The reactive compounds were further tested for their stability and for their reactivity in model reactions; some were found suitable as structural probes to investigate the binding site and the docking mode of ifenprodil in the NR2B subunit.
|
Inhibition of NR1/NR2B receptor expressed in xenopus oocytes assessed as effect on L-glutamate and glycine-induced current response
|
None
|
110.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Reactive derivatives for affinity labeling in the ifenprodil site of NMDA receptors.
Year : 2008
Volume : 18
Issue : 9
First Page : 2765
Last Page : 2770
Authors : Alarcon K, Martz A, Mony L, Neyton J, Paoletti P, Goeldner M, Foucaud B.
Abstract : To prepare thiol-reactive ifenprodil derivatives designed as potential probes for cysteine-substituted NR2B containing NMDA receptors, electrophilic centers were introduced in different areas of the ifenprodil structure. Intermediates and final compounds were evaluated by binding studies and by electrophysiology to determine the structural requirements for their selectivity. The reactive compounds were further tested for their stability and for their reactivity in model reactions; some were found suitable as structural probes to investigate the binding site and the docking mode of ifenprodil in the NR2B subunit.
|
Displacement of [3H](-)-(S)-emopamil from EBP in guinea pig liver membrane
|
Cavia porcellus
|
16.4
nM
|
|
Journal : J. Med. Chem.
Title : Novel 4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines as Delta(8)-Delta(7) sterol isomerase (emopamil binding protein) selective ligands with antiproliferative activity.
Year : 2008
Volume : 51
Issue : 23
First Page : 7523
Last Page : 7531
Authors : Berardi F, Abate C, Ferorelli S, de Robertis AF, Leopoldo M, Colabufo NA, Niso M, Perrone R.
Abstract : To find Delta(8)-Delta(7) sterol isomerase (EBP) selective ligands, various arylpiperazines previously studied and structurally related to some sigma receptors ligands were preliminarily screened. Consequently, a novel series of 2- or 2,6-disubstituted (CH(3), CH(3)O, Cl, F) cis- and trans-4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines was developed. Radioreceptor binding assays evidenced cis-19, cis-30 and cis-33 as new ligands with nanomolar affinity toward EBP site and a good selectivity relative to EBP-related sigma receptors. The most selective 2,6-dimethoxy derivative (cis-33) demonstrated the highest potency (EC(50) = 12.9 microM) and efficacy (70%) in inhibiting proliferation of human prostate cancer PC-3 cell line. Among the reference compounds, sigma(2) agonist 36 (PB28) reached the maximum efficacy (100%), suggesting the contribution of the sigma(2) receptor to the antiproliferative activity. This novel class of EBP inhibitors represents a valuable tool for investigating the last steps of cholesterol biosynthesis and related pathologies, as well as a starting point for developing new anticancer drugs.
|
Displacement of [3H](+)-pentazocine from sigma 1 receptor in guinea pig brain membrane without cerebellum
|
Cavia porcellus
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel 4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines as Delta(8)-Delta(7) sterol isomerase (emopamil binding protein) selective ligands with antiproliferative activity.
Year : 2008
Volume : 51
Issue : 23
First Page : 7523
Last Page : 7531
Authors : Berardi F, Abate C, Ferorelli S, de Robertis AF, Leopoldo M, Colabufo NA, Niso M, Perrone R.
Abstract : To find Delta(8)-Delta(7) sterol isomerase (EBP) selective ligands, various arylpiperazines previously studied and structurally related to some sigma receptors ligands were preliminarily screened. Consequently, a novel series of 2- or 2,6-disubstituted (CH(3), CH(3)O, Cl, F) cis- and trans-4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines was developed. Radioreceptor binding assays evidenced cis-19, cis-30 and cis-33 as new ligands with nanomolar affinity toward EBP site and a good selectivity relative to EBP-related sigma receptors. The most selective 2,6-dimethoxy derivative (cis-33) demonstrated the highest potency (EC(50) = 12.9 microM) and efficacy (70%) in inhibiting proliferation of human prostate cancer PC-3 cell line. Among the reference compounds, sigma(2) agonist 36 (PB28) reached the maximum efficacy (100%), suggesting the contribution of the sigma(2) receptor to the antiproliferative activity. This novel class of EBP inhibitors represents a valuable tool for investigating the last steps of cholesterol biosynthesis and related pathologies, as well as a starting point for developing new anticancer drugs.
|
Displacement of [3H]-DTG from sigma 2-type opioid receptor in rat liver membrane in presence of (+)-pentazocine
|
Rattus norvegicus
|
2.3
nM
|
|
Journal : J. Med. Chem.
Title : Novel 4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines as Delta(8)-Delta(7) sterol isomerase (emopamil binding protein) selective ligands with antiproliferative activity.
Year : 2008
Volume : 51
Issue : 23
First Page : 7523
Last Page : 7531
Authors : Berardi F, Abate C, Ferorelli S, de Robertis AF, Leopoldo M, Colabufo NA, Niso M, Perrone R.
Abstract : To find Delta(8)-Delta(7) sterol isomerase (EBP) selective ligands, various arylpiperazines previously studied and structurally related to some sigma receptors ligands were preliminarily screened. Consequently, a novel series of 2- or 2,6-disubstituted (CH(3), CH(3)O, Cl, F) cis- and trans-4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines was developed. Radioreceptor binding assays evidenced cis-19, cis-30 and cis-33 as new ligands with nanomolar affinity toward EBP site and a good selectivity relative to EBP-related sigma receptors. The most selective 2,6-dimethoxy derivative (cis-33) demonstrated the highest potency (EC(50) = 12.9 microM) and efficacy (70%) in inhibiting proliferation of human prostate cancer PC-3 cell line. Among the reference compounds, sigma(2) agonist 36 (PB28) reached the maximum efficacy (100%), suggesting the contribution of the sigma(2) receptor to the antiproliferative activity. This novel class of EBP inhibitors represents a valuable tool for investigating the last steps of cholesterol biosynthesis and related pathologies, as well as a starting point for developing new anticancer drugs.
|
Antiproliferative activity against human PC3 cells expressing EBP after 48 hrs by MTT assay
|
Homo sapiens
|
25.8
nM
|
|
Journal : J. Med. Chem.
Title : Novel 4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines as Delta(8)-Delta(7) sterol isomerase (emopamil binding protein) selective ligands with antiproliferative activity.
Year : 2008
Volume : 51
Issue : 23
First Page : 7523
Last Page : 7531
Authors : Berardi F, Abate C, Ferorelli S, de Robertis AF, Leopoldo M, Colabufo NA, Niso M, Perrone R.
Abstract : To find Delta(8)-Delta(7) sterol isomerase (EBP) selective ligands, various arylpiperazines previously studied and structurally related to some sigma receptors ligands were preliminarily screened. Consequently, a novel series of 2- or 2,6-disubstituted (CH(3), CH(3)O, Cl, F) cis- and trans-4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines was developed. Radioreceptor binding assays evidenced cis-19, cis-30 and cis-33 as new ligands with nanomolar affinity toward EBP site and a good selectivity relative to EBP-related sigma receptors. The most selective 2,6-dimethoxy derivative (cis-33) demonstrated the highest potency (EC(50) = 12.9 microM) and efficacy (70%) in inhibiting proliferation of human prostate cancer PC-3 cell line. Among the reference compounds, sigma(2) agonist 36 (PB28) reached the maximum efficacy (100%), suggesting the contribution of the sigma(2) receptor to the antiproliferative activity. This novel class of EBP inhibitors represents a valuable tool for investigating the last steps of cholesterol biosynthesis and related pathologies, as well as a starting point for developing new anticancer drugs.
|
Inhibition of rat recombinant NR1/NR2B receptor expressed in Xenopus oocytes assessed as inhibition of glutamate and glycine-induced evoked current by two electrode voltage clamp method
|
Rattus norvegicus
|
73.0
nM
|
|
Journal : J. Med. Chem.
Title : Enantiomeric propanolamines as selective N-methyl-D-aspartate 2B receptor antagonists.
Year : 2008
Volume : 51
Issue : 18
First Page : 5506
Last Page : 5521
Authors : Tahirovic YA, Geballe M, Gruszecka-Kowalik E, Myers SJ, Lyuboslavsky P, Le P, French A, Irier H, Choi WB, Easterling K, Yuan H, Wilson LJ, Kotloski R, McNamara JO, Dingledine R, Liotta DC, Traynelis SF, Snyder JP.
Abstract : Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11-64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC 50 values between 30-100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.
|
Displacement of [3H]ifenprodil from NMDA NR2B receptor in Wistar rat cerebral cortex membrane
|
Rattus norvegicus
|
20.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Development of 3-substituted-1H-indole derivatives as NR2B/NMDA receptor antagonists.
Year : 2009
Volume : 17
Issue : 4
First Page : 1640
Last Page : 1647
Authors : Gitto R, De Luca L, Ferro S, Citraro R, De Sarro G, Costa L, Ciranna L, Chimirri A.
Abstract : A combined ligand-based and structure-based approach has previously allowed us to identify NR2B/NMDA receptor antagonists containing indole scaffold. In order to further explore the main structure activity relationships of this class of derivatives we herein report the design, synthesis and biological evaluation of new analogues. Some derivatives demonstrated to produce significant anticonvulsant properties and NMDA antagonism. The most active of them (3d) showed NR2B binding affinity equipotent to that of ifenprodil. These results were also corroborated by computational studies.
|
Displacement of [3H](+)-pentazocine from sigma1 receptor in rat liver membrane by liquid scintillation counting
|
Rattus norvegicus
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, biological evaluation, and three-dimensional in silico pharmacophore model for sigma(1) receptor ligands based on a series of substituted benzo[d]oxazol-2(3H)-one derivatives.
Year : 2009
Volume : 52
Issue : 17
First Page : 5380
Last Page : 5393
Authors : Zampieri D, Mamolo MG, Laurini E, Florio C, Zanette C, Fermeglia M, Posocco P, Paneni MS, Pricl S, Vio L.
Abstract : Novel benzo[d]oxazol-2(3H)-one derivatives were designed and synthesized, and their affinities against sigma receptors were evaluated. On the basis of 31 compounds, a three-dimensional pharmacophore model for the sigma(1) receptor binding site was developed using the Catalyst 4.9 software package. The best 3D pharmacophore hypothesis, consisting of one positive ionizable, one hydrogen bond acceptor, two hydrophobic aromatic, and one hydrophobic features provided a 3D-QSAR model with a correlation coefficient of 0.89. The best hypothesis was also validated by three independent methods, i.e., the Fisher randomization test included in the CatScramble functionality of Catalyst, the leave-one-out test, and activity prediction of an additional test set. The achieved results will allow researchers to use this 3D pharmacophore model for the design and synthesis of a second generation of high affinity sigma(1) ligands, as well as to discover other lead compounds for this class of receptors.
|
Displacement of [3H](+/-)-emopamil from EBP in Dunkin guinea pig liver membrane by radioreceptor binding assay
|
Cavia porcellus
|
10.2
nM
|
|
Journal : J. Med. Chem.
Title : Exploring the importance of piperazine N-atoms for sigma(2) receptor affinity and activity in a series of analogs of 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28).
Year : 2009
Volume : 52
Issue : 23
First Page : 7817
Last Page : 7828
Authors : Berardi F, Abate C, Ferorelli S, Uricchio V, Colabufo NA, Niso M, Perrone R.
Abstract : sigma(2)-Agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (7, PB 28), which proved to revert doxorubicin resistance in breast cancer cells, was taken as a template to prepare new analogs. One of the two basic N-atoms was alternatively replaced by a methine or converted into an amide or ammonium function, with the aim of finding out which of them was essential for sigma(2) receptor affinity and activity. Some simply 4-substituted 1-cyclohexylpiperazines were also investigated. None of the compounds was as high-affinity as 7 (sigma(2)K(i) = 0.68, sigma(1)K(i) = 0.38 nM), proving that both basic N-atoms ensure better sigma(2) receptor binding. Amide 36 emerged as high-affinity (K(i) = 0.11 nM) and noteworthy() selective (1627-fold) sigma(1) ligand. Small N-cyclohexylpiperazine 59 displayed the highest sigma(2) affinity (K(i) = 4.70 nM). The sigma(2)/sigma(1) selectivities were generally low. Antiproliferative assay in SK-N-SH cells revealed piperidines 24 and 15 as putative sigma(2) agonists (EC(50)s 1.40 and 3.64 muM respectively) more potent than 7.
|
Antagonist activity at wild type NR1/NR2B receptor expressed in Xenopus oocytes assessed as inhibition of agonist-induced current amplitude by two-electrode voltage-clamp method
|
None
|
190.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of a novel NR2B-selective NMDA receptor antagonist using a virtual screening approach.
Year : 2010
Volume : 20
Issue : 18
First Page : 5552
Last Page : 5558
Authors : Mony L, Triballeau N, Paoletti P, Acher FC, Bertrand HO.
Abstract : We report the identification of a novel NR2B-selective NMDAR antagonist with an original scaffold, LSP10-0500. This compound was identified by a virtual high-throughput screening approach on the basis of a quantitative pharmacophore model of NR2B-specific NMDAR antagonists. A SAR study around LSP10-0500 is also described.
|
Antagonist activity at wild type NR1/NR2B receptor expressed in Xenopus oocytes assessed as inhibition of agonist-induced current amplitude at 10 uM by two-electrode voltage-clamp method
|
None
|
0.94
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of a novel NR2B-selective NMDA receptor antagonist using a virtual screening approach.
Year : 2010
Volume : 20
Issue : 18
First Page : 5552
Last Page : 5558
Authors : Mony L, Triballeau N, Paoletti P, Acher FC, Bertrand HO.
Abstract : We report the identification of a novel NR2B-selective NMDAR antagonist with an original scaffold, LSP10-0500. This compound was identified by a virtual high-throughput screening approach on the basis of a quantitative pharmacophore model of NR2B-specific NMDAR antagonists. A SAR study around LSP10-0500 is also described.
|
Antiproliferative activity against human fetal neural precursor cells by MTT assay
|
Homo sapiens
|
420.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical genetics reveals a complex functional ground state of neural stem cells.
Year : 2007
Volume : 3
Issue : 5
First Page : 268
Last Page : 273
Authors : Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, Ling EK, Ward RJ, Jamieson LG, Tyers M, Dirks PB.
Abstract : The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.
|
Antiproliferative activity against human GBM2 cells by MTT assay
|
Homo sapiens
|
206.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical genetics reveals a complex functional ground state of neural stem cells.
Year : 2007
Volume : 3
Issue : 5
First Page : 268
Last Page : 273
Authors : Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, Ling EK, Ward RJ, Jamieson LG, Tyers M, Dirks PB.
Abstract : The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.
|
Displacement of [3H]ifenprodil from NR2B receptor in rat cortical synaptic membranes
|
Rattus norvegicus
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of radio-iodinated benzimidazoles as SPECT imaging agents for NR2B subtype of NMDA receptor.
Year : 2010
Volume : 18
Issue : 21
First Page : 7497
Last Page : 7506
Authors : Fuchigami T, Yamaguchi H, Ogawa M, Biao L, Nakayama M, Haratake M, Magata Y.
Abstract : In this study, the benzimidazole derivatives were synthesized and evaluated as imaging agents for the NR2B subtype of NMDA receptor. Among these ligands, 2-{[4-(4-iodobenzyl)piperidin-1-yl]methyl}benzimidazol-5-ol (8) and N-{2-[4-(4-iodobenzyl)-piperidin-1-ylmethyl]benzoimidazol-5-yl}-methanesulfonamide (9) exhibited high affinity for the NR2B subunit (K(i) values; 7.28 nM for 8 and 5.75 nM for 9). In vitro autoradiography experiments demonstrated high accumulation in the forebrain regions but low in the cerebellum for both [(125)I]8 and [(125)I]9. These regional distributions of the radioligands correlated with the expression of the NR2B subunit. The in vitro binding of these ligands was inhibited by NR2B antagonist but not by other site ligands, which suggested the high selectivity of [(125)I]8 and [(125)I]9 for the NR2B subunit. In mice, the regional brain uptakes of [(125)I]8 and [(125)I]9 at 5-180 min after administration were 0.42-0.56% and 0.44-0.67% dose/g, respectively. The brain-to-blood ratio of [(125)I]8 at 180 min was reduced by 34% in the presence of non-radioactive ligands and by 59% in the presence of the NR2B ligand Ro-25,6981. These results indicated that [(125)I]8 could be partially bound to the NR2B subunit in vivo. Although the brain uptake of these benzimidazole derivatives was too low to allow for in vivo SPECT imaging, these compounds might be useful scaffolds for the development of imaging probes specific for the NMDA receptors.
|
Displacement of [3H]ifenprodil from human recombinant NR1-1a/NR2B receptor expressed in mouse L(tk-) cells after 120 mins by scintillation counting
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Conformationally constrained NR2B selective NMDA receptor antagonists derived from ifenprodil: Synthesis and biological evaluation of tetrahydro-3-benzazepine-1,7-diols.
Year : 2010
Volume : 18
Issue : 22
First Page : 8005
Last Page : 8015
Authors : Tewes B, Frehland B, Schepmann D, Schmidtke KU, Winckler T, Wünsch B.
Abstract : NR2B selective NMDA receptor antagonists with tetrahydro-3-benzazepine-1,7-diol scaffold have been designed by formal cleavage and reconstitution of the piperidine ring of the lead compound ifenprodil (1). The secondary amine 10 represents the central building block for the synthesis of more than 25 tetrahydro-3-benzazepin-1-ols. Generally 7-hydroxy derivatives display higher NR2B receptor affinities than the corresponding 7-benzyloxy compounds. A distance of four atoms (five bond lengths) between the basic amino group and the terminal aryl moiety led to highest NR2B affinity. 3-(4-Phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol (WMS-1410, 25) represents the most promising NR2B antagonist of this series showing a K(i)-value of 14nM. Compound 25 reveals excellent selectivity over more than 100 further relevant target proteins, antagonizes glutamate induced excitotoxicity (IC(50)=18.4nM) and is metabolically more stable than ifenprodil. Up to a dose of 100mg/kg 25 is well tolerated by mice and it shows dose dependent analgesic activity in the late neuropathic pain phase of the formalin assay.
|
Displacement of [3H](+)-pentazocine from sigma1 receptor guinea pig brain after 180 mins scintillation counting
|
Cavia porcellus
|
125.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Conformationally constrained NR2B selective NMDA receptor antagonists derived from ifenprodil: Synthesis and biological evaluation of tetrahydro-3-benzazepine-1,7-diols.
Year : 2010
Volume : 18
Issue : 22
First Page : 8005
Last Page : 8015
Authors : Tewes B, Frehland B, Schepmann D, Schmidtke KU, Winckler T, Wünsch B.
Abstract : NR2B selective NMDA receptor antagonists with tetrahydro-3-benzazepine-1,7-diol scaffold have been designed by formal cleavage and reconstitution of the piperidine ring of the lead compound ifenprodil (1). The secondary amine 10 represents the central building block for the synthesis of more than 25 tetrahydro-3-benzazepin-1-ols. Generally 7-hydroxy derivatives display higher NR2B receptor affinities than the corresponding 7-benzyloxy compounds. A distance of four atoms (five bond lengths) between the basic amino group and the terminal aryl moiety led to highest NR2B affinity. 3-(4-Phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol (WMS-1410, 25) represents the most promising NR2B antagonist of this series showing a K(i)-value of 14nM. Compound 25 reveals excellent selectivity over more than 100 further relevant target proteins, antagonizes glutamate induced excitotoxicity (IC(50)=18.4nM) and is metabolically more stable than ifenprodil. Up to a dose of 100mg/kg 25 is well tolerated by mice and it shows dose dependent analgesic activity in the late neuropathic pain phase of the formalin assay.
|
Displacement of [3H]di-o-tolylguanidine from sigma2 receptor rat liver membranes after 180 mins scintillation counting
|
Rattus norvegicus
|
98.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Conformationally constrained NR2B selective NMDA receptor antagonists derived from ifenprodil: Synthesis and biological evaluation of tetrahydro-3-benzazepine-1,7-diols.
Year : 2010
Volume : 18
Issue : 22
First Page : 8005
Last Page : 8015
Authors : Tewes B, Frehland B, Schepmann D, Schmidtke KU, Winckler T, Wünsch B.
Abstract : NR2B selective NMDA receptor antagonists with tetrahydro-3-benzazepine-1,7-diol scaffold have been designed by formal cleavage and reconstitution of the piperidine ring of the lead compound ifenprodil (1). The secondary amine 10 represents the central building block for the synthesis of more than 25 tetrahydro-3-benzazepin-1-ols. Generally 7-hydroxy derivatives display higher NR2B receptor affinities than the corresponding 7-benzyloxy compounds. A distance of four atoms (five bond lengths) between the basic amino group and the terminal aryl moiety led to highest NR2B affinity. 3-(4-Phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol (WMS-1410, 25) represents the most promising NR2B antagonist of this series showing a K(i)-value of 14nM. Compound 25 reveals excellent selectivity over more than 100 further relevant target proteins, antagonizes glutamate induced excitotoxicity (IC(50)=18.4nM) and is metabolically more stable than ifenprodil. Up to a dose of 100mg/kg 25 is well tolerated by mice and it shows dose dependent analgesic activity in the late neuropathic pain phase of the formalin assay.
|
Inhibition of human ERG
|
Homo sapiens
|
100.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Predicting hERG activities of compounds from their 3D structures: development and evaluation of a global descriptors based QSAR model.
Year : 2011
Volume : 46
Issue : 2
First Page : 618
Last Page : 630
Authors : Sinha N, Sen S.
Abstract : A QSAR based predictive model of hERG activity in terms of 'global descriptors' has been developed and evaluated. The QSAR was developed by training 77 compounds covering a wide range of activities and was validated based on an external 'test set' of 80 compounds using neural network method. Statistical parameters and examination of enrichment factor indicated the effectiveness of the present model. Randomization test demonstrated the robustness of the model and cross-validation test further validated the QSAR. Domain of applicability test indicated to the high degree of reliability of the predicted results. Satisfactory performance in classifying compounds into 'active' and 'inactive' groups was also obtained. The cases where the QSAR failed, the possible sources of errors have been discussed.
|
Antagonist activity against NR1a/NR2B receptor transfected in human HEK293 cells assessed as inhibition of NMDA-induced Ca2+ influx
|
None
|
177.4
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, evaluation and metabolic studies of radiotracers containing a 4-(4-[18F]-fluorobenzyl)piperidin-1-yl moiety for the PET imaging of NR2B NMDA receptors.
Year : 2011
Volume : 46
Issue : 6
First Page : 2295
Last Page : 2309
Authors : Labas R, Gilbert G, Nicole O, Dhilly M, Abbas A, Tirel O, Buisson A, Henry J, Barré L, Debruyne D, Sobrio F.
Abstract : In this study, novel specific PET radioligands containing the 4-(4-fluorobenzyl)piperidine moiety and selectively antagonistic for the NR2B subunit containing NMDA receptors were developed. Two antagonists, RGH-896 (1a) and 4-(4-fluorobenzyl)piperidinyl-1-methyl-2-benzimidazol-5-ol (2a), belonging to two different structural families, were radiolabeled by an aromatic nucleophilic radiofluorination followed by a reduction of the para-position carbonyl function. Radiotracers [18F]1a, [18F]2a or the pattern 4-(4-[18F]-fluorobenzyl)piperidine ([18F]6) demonstrated an identical in vivo behavior with high accumulation of radioactivity in bone and cartilage which would suggest a radiodefluorination of the radiotracers. The identification of metabolites from 6 by LC-MS-MS confirmed the significant degree of defluorination as a result of the in vivo hydroxylation in the benzyl ring. In conclusion, [18F]1a or [18F]2a are not suitable for imaging the NR2B NMDA receptors due to their poor brain penetration. We also argue for a cautious use of the radiolabeled pattern, 4-(4-[18F]-fluorobenzyl)piperidine, to develop PET radiotracers.
|
Antagonist activity against NR1a/NR2A receptor transfected in human HEK293 cells assessed as inhibition of NMDA-induced Ca2+ influx at 10 uM
|
None
|
22.27
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, evaluation and metabolic studies of radiotracers containing a 4-(4-[18F]-fluorobenzyl)piperidin-1-yl moiety for the PET imaging of NR2B NMDA receptors.
Year : 2011
Volume : 46
Issue : 6
First Page : 2295
Last Page : 2309
Authors : Labas R, Gilbert G, Nicole O, Dhilly M, Abbas A, Tirel O, Buisson A, Henry J, Barré L, Debruyne D, Sobrio F.
Abstract : In this study, novel specific PET radioligands containing the 4-(4-fluorobenzyl)piperidine moiety and selectively antagonistic for the NR2B subunit containing NMDA receptors were developed. Two antagonists, RGH-896 (1a) and 4-(4-fluorobenzyl)piperidinyl-1-methyl-2-benzimidazol-5-ol (2a), belonging to two different structural families, were radiolabeled by an aromatic nucleophilic radiofluorination followed by a reduction of the para-position carbonyl function. Radiotracers [18F]1a, [18F]2a or the pattern 4-(4-[18F]-fluorobenzyl)piperidine ([18F]6) demonstrated an identical in vivo behavior with high accumulation of radioactivity in bone and cartilage which would suggest a radiodefluorination of the radiotracers. The identification of metabolites from 6 by LC-MS-MS confirmed the significant degree of defluorination as a result of the in vivo hydroxylation in the benzyl ring. In conclusion, [18F]1a or [18F]2a are not suitable for imaging the NR2B NMDA receptors due to their poor brain penetration. We also argue for a cautious use of the radiolabeled pattern, 4-(4-[18F]-fluorobenzyl)piperidine, to develop PET radiotracers.
|
Antagonist activity against NR1/NR2B receptor expressed in xenopus oocytes assessed as inhibition of NMDA induced Ca2+ influx
|
None
|
340.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, evaluation and metabolic studies of radiotracers containing a 4-(4-[18F]-fluorobenzyl)piperidin-1-yl moiety for the PET imaging of NR2B NMDA receptors.
Year : 2011
Volume : 46
Issue : 6
First Page : 2295
Last Page : 2309
Authors : Labas R, Gilbert G, Nicole O, Dhilly M, Abbas A, Tirel O, Buisson A, Henry J, Barré L, Debruyne D, Sobrio F.
Abstract : In this study, novel specific PET radioligands containing the 4-(4-fluorobenzyl)piperidine moiety and selectively antagonistic for the NR2B subunit containing NMDA receptors were developed. Two antagonists, RGH-896 (1a) and 4-(4-fluorobenzyl)piperidinyl-1-methyl-2-benzimidazol-5-ol (2a), belonging to two different structural families, were radiolabeled by an aromatic nucleophilic radiofluorination followed by a reduction of the para-position carbonyl function. Radiotracers [18F]1a, [18F]2a or the pattern 4-(4-[18F]-fluorobenzyl)piperidine ([18F]6) demonstrated an identical in vivo behavior with high accumulation of radioactivity in bone and cartilage which would suggest a radiodefluorination of the radiotracers. The identification of metabolites from 6 by LC-MS-MS confirmed the significant degree of defluorination as a result of the in vivo hydroxylation in the benzyl ring. In conclusion, [18F]1a or [18F]2a are not suitable for imaging the NR2B NMDA receptors due to their poor brain penetration. We also argue for a cautious use of the radiolabeled pattern, 4-(4-[18F]-fluorobenzyl)piperidine, to develop PET radiotracers.
|
Antagonist activity at NR1/NR2B receptor assessed as inhibition of Glu/Gly induced Ca2+ influx
|
None
|
66.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, evaluation and metabolic studies of radiotracers containing a 4-(4-[18F]-fluorobenzyl)piperidin-1-yl moiety for the PET imaging of NR2B NMDA receptors.
Year : 2011
Volume : 46
Issue : 6
First Page : 2295
Last Page : 2309
Authors : Labas R, Gilbert G, Nicole O, Dhilly M, Abbas A, Tirel O, Buisson A, Henry J, Barré L, Debruyne D, Sobrio F.
Abstract : In this study, novel specific PET radioligands containing the 4-(4-fluorobenzyl)piperidine moiety and selectively antagonistic for the NR2B subunit containing NMDA receptors were developed. Two antagonists, RGH-896 (1a) and 4-(4-fluorobenzyl)piperidinyl-1-methyl-2-benzimidazol-5-ol (2a), belonging to two different structural families, were radiolabeled by an aromatic nucleophilic radiofluorination followed by a reduction of the para-position carbonyl function. Radiotracers [18F]1a, [18F]2a or the pattern 4-(4-[18F]-fluorobenzyl)piperidine ([18F]6) demonstrated an identical in vivo behavior with high accumulation of radioactivity in bone and cartilage which would suggest a radiodefluorination of the radiotracers. The identification of metabolites from 6 by LC-MS-MS confirmed the significant degree of defluorination as a result of the in vivo hydroxylation in the benzyl ring. In conclusion, [18F]1a or [18F]2a are not suitable for imaging the NR2B NMDA receptors due to their poor brain penetration. We also argue for a cautious use of the radiolabeled pattern, 4-(4-[18F]-fluorobenzyl)piperidine, to develop PET radiotracers.
|
Displacement of [3H]-emopamil from delta(8)-delta(7) sterol isomerase in guinea pig liver membranes
|
Cavia porcellus
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and binding assays of novel 3,3-dimethylpiperidine derivatives with various lipophilicities as σ₁ receptor ligands.
Year : 2011
Volume : 19
Issue : 24
First Page : 7612
Last Page : 7622
Authors : Ferorelli S, Abate C, Pedone MP, Colabufo NA, Contino M, Perrone R, Berardi F.
Abstract : Starting from two carbocyclic analogs, a series of 3,3-dimethylpiperidine derivatives was prepared and tested in radioligand binding assays at σ(1) and σ(2) receptors, and at Δ(8)-Δ(7) sterol isomerase (SI) site. The novel compounds mostly bear heterocyclic rings or bicyclic nucleus of differing lipophilicities. Compounds 18a and 19a,b demonstrated the highest σ(1) affinity (K(i)=0.14-0.38 nM) with a good selectivity versus σ(2) binding. Among them, 18a had the lowest ClogD value (3.01) and only 19b was selective versus SI too. Generally, it was observed that more planar and hydrophilic heteronuclei conferred a decrease in affinity for both σ receptor subtypes.
|
Neuroprotective activity in human SH-SY5Y cells assessed as protection against NMDA-induced cell death after 6 hrs by MTS assay
|
Homo sapiens
|
0.73
nM
|
|
Journal : J. Med. Chem.
Title : Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease.
Year : 2012
Volume : 55
Issue : 22
First Page : 9708
Last Page : 9721
Authors : Simoni E, Daniele S, Bottegoni G, Pizzirani D, Trincavelli ML, Goldoni L, Tarozzo G, Reggiani A, Martini C, Piomelli D, Melchiorre C, Rosini M, Cavalli A.
Abstract : Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM).
|
Displacement of [3H]Ifenprodil from NMDAR-2B in Sprague-Dawley rat frontal cortex homogenates after 2 hrs by liquid scintillation counting
|
Rattus norvegicus
|
29.0
nM
|
|
Journal : J. Med. Chem.
Title : Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer's disease.
Year : 2012
Volume : 55
Issue : 22
First Page : 9708
Last Page : 9721
Authors : Simoni E, Daniele S, Bottegoni G, Pizzirani D, Trincavelli ML, Goldoni L, Tarozzo G, Reggiani A, Martini C, Piomelli D, Melchiorre C, Rosini M, Cavalli A.
Abstract : Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM).
|
Displacement of [3H]ifenprodil from NMDA receptor GluN2B subunit in Wistar rat cerebral cortex after 120 mins
|
Rattus norvegicus
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological characterization of 3-substituted 1H-indoles as ligands of GluN2B-containing N-methyl-D-aspartate receptors. Part 2.
Year : 2012
Volume : 55
Issue : 23
First Page : 10532
Last Page : 10539
Authors : Gitto R, De Luca L, Ferro S, Buemi MR, Russo E, De Sarro G, Chisari M, Ciranna L, Chimirri A.
Abstract : In the course of the identification of new indole derivatives targeting GluN2B-subunit-containing N-methyl-D-aspartate (NMDA) receptor, the (N-1H-indol-6-methanesulfonamide-3-yl)-2-(4-benzylpiperidin-1-yl)ethanone (10b) was identified as a potent ligand for this NMDA receptor subunit. It displays very high binding affinity (IC50 of 8.9 nmol) for displacement of [3H]ifenprodil, thus showing improved potency with respect to the previously reported analogues as confirmed by functional assay. This finding was consistent with the docking pose of compound 10b within the binding pocket localized in the GluN1-GluN2B subunit interface of NMDA receptor tetraheteromeric complex.
|
Inhibition of GluN1/GluN2B receptor (unknown origin) expressed in Xenopus oocytes by voltage clamp assay
|
Homo sapiens
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : Target- and mechanism-based therapeutics for neurodegenerative diseases: strength in numbers.
Year : 2013
Volume : 56
Issue : 8
First Page : 3121
Last Page : 3147
Authors : Trippier PC, Jansen Labby K, Hawker DD, Mataka JJ, Silverman RB.
Abstract : The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this Perspective we examine recent progress in the areas of neurodegenerative drug discovery, focusing on some of the most common targets and mechanisms: N-methyl-d-aspartic acid (NMDA) receptors, voltage gated calcium channels (VGCCs), neuronal nitric oxide synthase (nNOS), oxidative stress from reactive oxygen species, and protein aggregation. These represent the key players identified in neurodegeneration and are part of a complex, intertwined signaling cascade. The synergistic delivery of two or more compounds directed against these targets, along with the design of small molecules with multiple modes of action, should be explored in pursuit of more effective clinical treatments for neurodegenerative diseases.
|
Displacement of [3H]DTG from guinea pig brain sigma2 receptor after 120 mins by scintillation counting analysis in presence of SKF10,047
|
Cavia porcellus
|
18.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : From NMDA receptor antagonists to discovery of selective σ₂ receptor ligands.
Year : 2014
Volume : 22
Issue : 1
First Page : 393
Last Page : 397
Authors : Gitto R, De Luca L, Ferro S, Scala A, Ronsisvalle S, Parenti C, Prezzavento O, Buemi MR, Chimirri A.
Abstract : Following previous studies focused on the search for new molecules targeting GluN2B-containing NMDA, a small series of 1-(1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone derivatives has been synthesized by using Microwave Assisted Organic Synthesis (MAOS). Given that GluN2B ligands frequently exert off-target effects we also tested their affinity towards sigma receptors. Binding assay revealed that only the 1-(5-hydroxy-1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone (7a) retained GluN2B affinity. Interestingly, the 5-methoxyindoles 5a and 6a were efficient and selective ligands toward σ₂ receptor (Ki values of 10nM and 20 nM, respectively). Thus, in this case the discovery of new σ₂ receptor selective ligands was an unexpected result emerging from the screening of cross-activity against other CNS receptors.
|
Displacement of [3H]-(+)-pentazocine from guinea pig brain sigma1 receptor after 150 mins by scintillation counting analysis
|
Cavia porcellus
|
1.02
nM
|
|
Journal : Bioorg. Med. Chem.
Title : From NMDA receptor antagonists to discovery of selective σ₂ receptor ligands.
Year : 2014
Volume : 22
Issue : 1
First Page : 393
Last Page : 397
Authors : Gitto R, De Luca L, Ferro S, Scala A, Ronsisvalle S, Parenti C, Prezzavento O, Buemi MR, Chimirri A.
Abstract : Following previous studies focused on the search for new molecules targeting GluN2B-containing NMDA, a small series of 1-(1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone derivatives has been synthesized by using Microwave Assisted Organic Synthesis (MAOS). Given that GluN2B ligands frequently exert off-target effects we also tested their affinity towards sigma receptors. Binding assay revealed that only the 1-(5-hydroxy-1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone (7a) retained GluN2B affinity. Interestingly, the 5-methoxyindoles 5a and 6a were efficient and selective ligands toward σ₂ receptor (Ki values of 10nM and 20 nM, respectively). Thus, in this case the discovery of new σ₂ receptor selective ligands was an unexpected result emerging from the screening of cross-activity against other CNS receptors.
|
Displacement of [3H]ifenprodil from Wistar rat cerebral cortex glutamate NMDA receptor GluN2B subunit after 120 mins by scintillation counting analysis
|
Rattus norvegicus
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : From NMDA receptor antagonists to discovery of selective σ₂ receptor ligands.
Year : 2014
Volume : 22
Issue : 1
First Page : 393
Last Page : 397
Authors : Gitto R, De Luca L, Ferro S, Scala A, Ronsisvalle S, Parenti C, Prezzavento O, Buemi MR, Chimirri A.
Abstract : Following previous studies focused on the search for new molecules targeting GluN2B-containing NMDA, a small series of 1-(1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone derivatives has been synthesized by using Microwave Assisted Organic Synthesis (MAOS). Given that GluN2B ligands frequently exert off-target effects we also tested their affinity towards sigma receptors. Binding assay revealed that only the 1-(5-hydroxy-1H-indol-3-yl)-2-(4-phenylpiperidin-1-yl)ethanone (7a) retained GluN2B affinity. Interestingly, the 5-methoxyindoles 5a and 6a were efficient and selective ligands toward σ₂ receptor (Ki values of 10nM and 20 nM, respectively). Thus, in this case the discovery of new σ₂ receptor selective ligands was an unexpected result emerging from the screening of cross-activity against other CNS receptors.
|
Displacement of [3H]Ifenprodil from NMDA receptor GluN2B subunit in Wistar rat cerebral cortex
|
Rattus norvegicus
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, modelling and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-d-aspartate receptors.
Year : 2014
Volume : 22
Issue : 3
First Page : 1040
Last Page : 1048
Authors : Gitto R, De Luca L, Ferro S, Russo E, De Sarro G, Chisari M, Ciranna L, Alvarez-Builla J, Alajarin R, Buemi MR, Chimirri A.
Abstract : A three-step synthetic pathway has been employed to synthesize a small library of 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethanone and 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethane-1,2-dione derivatives that have been screened in [(3)H]ifenprodil competition binding assay. Some compounds exhibited significant binding affinity at nanomolar concentration, the most active being ligand 35 (IC50=5.5nM). Docking experiments suggested the main interactions between 35 and GluN2B-containing NMDA receptors. Notably, the compound 35 reduced NMDA-mediated excitatory post-synaptic currents recorded in mouse hippocampal slices indicating antagonistic effects (50nM). Moreover, the compound 35 has shown antioxidant effects in a preliminary screening, thus suggesting that it might be considered prototype for future drug development of novel 'dual target' neuroprotective agents.
|
Inhibition of NMDA receptor GluN2B subunit (unknown origin)
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, modelling and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-d-aspartate receptors.
Year : 2014
Volume : 22
Issue : 3
First Page : 1040
Last Page : 1048
Authors : Gitto R, De Luca L, Ferro S, Russo E, De Sarro G, Chisari M, Ciranna L, Alvarez-Builla J, Alajarin R, Buemi MR, Chimirri A.
Abstract : A three-step synthetic pathway has been employed to synthesize a small library of 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethanone and 2-(4-arylpiperidin-1-yl)-1-(1H-indol-3-yl)ethane-1,2-dione derivatives that have been screened in [(3)H]ifenprodil competition binding assay. Some compounds exhibited significant binding affinity at nanomolar concentration, the most active being ligand 35 (IC50=5.5nM). Docking experiments suggested the main interactions between 35 and GluN2B-containing NMDA receptors. Notably, the compound 35 reduced NMDA-mediated excitatory post-synaptic currents recorded in mouse hippocampal slices indicating antagonistic effects (50nM). Moreover, the compound 35 has shown antioxidant effects in a preliminary screening, thus suggesting that it might be considered prototype for future drug development of novel 'dual target' neuroprotective agents.
|
Displacement of [3H]ifenprodil from human GluN2B expressed in mouse L(tk-) cells co-expressing GluN1a after 120 mins by scintillation counting method
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, GluN2B affinity and selectivity of benzo[7]annulen-7-amines.
Year : 2014
Volume : 22
Issue : 23
First Page : 6638
Last Page : 6646
Authors : Gawaskar S, Schepmann D, Bonifazi A, Wünsch B.
Abstract : Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7-one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)3 led to the secondary amines 6a-d, cis-6h and trans-6i. The tertiary amines 6e-g were obtained by SN2-substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5-position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4-benzylpiperidine 6g show the highest GluN2B affinities (Ki=2.3nM and 2.9nM, respectively). With respect to selectivity against the PCP binding site, σ1 and σ2 receptors the phenylpiperazine 6f is the most promising GluN2B antagonist.
|
Displacement of [3H](+)-pentazocine from sigma1 receptor in guinea pig brain membranes after 180 mins by scintillation counting method
|
Cavia porcellus
|
125.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, GluN2B affinity and selectivity of benzo[7]annulen-7-amines.
Year : 2014
Volume : 22
Issue : 23
First Page : 6638
Last Page : 6646
Authors : Gawaskar S, Schepmann D, Bonifazi A, Wünsch B.
Abstract : Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7-one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)3 led to the secondary amines 6a-d, cis-6h and trans-6i. The tertiary amines 6e-g were obtained by SN2-substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5-position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4-benzylpiperidine 6g show the highest GluN2B affinities (Ki=2.3nM and 2.9nM, respectively). With respect to selectivity against the PCP binding site, σ1 and σ2 receptors the phenylpiperazine 6f is the most promising GluN2B antagonist.
|
Displacement of [3H]DTG from sigma2 receptor in rat liver membranes after 180 mins by scintillation counting method
|
Rattus norvegicus
|
98.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, GluN2B affinity and selectivity of benzo[7]annulen-7-amines.
Year : 2014
Volume : 22
Issue : 23
First Page : 6638
Last Page : 6646
Authors : Gawaskar S, Schepmann D, Bonifazi A, Wünsch B.
Abstract : Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7-one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)3 led to the secondary amines 6a-d, cis-6h and trans-6i. The tertiary amines 6e-g were obtained by SN2-substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5-position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4-benzylpiperidine 6g show the highest GluN2B affinities (Ki=2.3nM and 2.9nM, respectively). With respect to selectivity against the PCP binding site, σ1 and σ2 receptors the phenylpiperazine 6f is the most promising GluN2B antagonist.
|
Displacement of [3H]ifenprodil from Wistar rat cerebral cortex GluN2B receptor after 120 mins
|
Rattus norvegicus
|
47.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-guided design of new indoles as negative allosteric modulators (NAMs) of N-methyl-D-aspartate receptor (NMDAR) containing GluN2B subunit.
Year : 2016
Volume : 24
Issue : 7
First Page : 1513
Last Page : 1519
Authors : Buemi MR, De Luca L, Ferro S, Russo E, De Sarro G, Gitto R.
Abstract : Negative allosteric modulators (NAMs) of GluN2B-containing NMDARs provide pharmacological tools for the treatment of chronic neurodegenerative diseases. Novel NAMs have been designed on the basis of computational studies focused on the 'hit compound' 3. This series of indoles has been tested in competition assay. Compounds 16 and 17 were the most active ligands (IC50 values of 83 nM and 71 nM, respectively) and they showed a potency close to that of reference compounds ifenprodil (1, IC50=47 nM) and 3 (IC50=25 nM). Furthermore, docking studies have been performed for active ligand 16 and the results were in a good agreement with biological data.
|
Displacement of [3H]-DTG from sigma 2 receptor in rat liver membranes after 120 mins by scintillation counting analysis
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : Bioorg Med Chem
Title : 2-Methyltetrahydro-3-benzazepin-1-ols - The missing link in SAR of GluN2B selective NMDA receptor antagonists.
Year : 2018
Volume : 26
Issue : 2
First Page : 501
Last Page : 508
Authors : Dey S, Schepmann D, Wünsch B.
Abstract : The NMDA receptor containing GluN2B subunits represents a promising target for the development of drugs for the treatment of various neurological disorders including neurodegenerative diseases. In order to study the role of CH3 and OH moieties trisubstituted tetrahydro-3-benzazepines 4 were designed as missing link between tetra- and disubstituted 3-benzazepines 2 and 5. The synthesis of 4 comprises eight reaction steps starting from alanine. The intramolecular Friedel-Crafts acylation to obtain the ketone 12 and the base-catalyzed elimination of trifluoromethanesulfinate (CF3SO2-) followed by NaBH4 reduction represent the key steps. The GluN2B affinity of the cis-configured 3-benzazepin-1-ol cis-4a with a 4-phenylbutyl side chain (Ki = 252 nM) is considerably lower than the GluN2B affinity of (R,R)-2 (Ki = 17 nM) indicating the importance of the phenolic OH moiety for the interaction with the receptor protein. Introduction of an additional CH3 moiety in 2-position led to a slight decrease of GluN2B affinity as can be seen by comparing the affinity data of cis-4a and 5. The homologous phenylpentyl derivative cis-4b shows the highest GluN2B affinity (Ki = 56 nM) of this series of compounds. According to docking studies cis-4a adopts the same binding mode as the cocrystallized ligand ifenprodil-keto 1A and 5 at the interface of the GluN2B and GluN1a subunits. The same crucial H-bonds are formed between the C(O)NH2 moiety of Gln110 within the GluN2B subunit and the protonated amino moiety and the OH moiety of (R,R)-cis-4a.
|
Displacement of [3H]-ifenprodil from recombinant human GluN1a/GluN2B expressed in L(tk-) cell membranes after 120 mins by scintillation counting analysis
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg Med Chem
Title : 2-Methyltetrahydro-3-benzazepin-1-ols - The missing link in SAR of GluN2B selective NMDA receptor antagonists.
Year : 2018
Volume : 26
Issue : 2
First Page : 501
Last Page : 508
Authors : Dey S, Schepmann D, Wünsch B.
Abstract : The NMDA receptor containing GluN2B subunits represents a promising target for the development of drugs for the treatment of various neurological disorders including neurodegenerative diseases. In order to study the role of CH3 and OH moieties trisubstituted tetrahydro-3-benzazepines 4 were designed as missing link between tetra- and disubstituted 3-benzazepines 2 and 5. The synthesis of 4 comprises eight reaction steps starting from alanine. The intramolecular Friedel-Crafts acylation to obtain the ketone 12 and the base-catalyzed elimination of trifluoromethanesulfinate (CF3SO2-) followed by NaBH4 reduction represent the key steps. The GluN2B affinity of the cis-configured 3-benzazepin-1-ol cis-4a with a 4-phenylbutyl side chain (Ki = 252 nM) is considerably lower than the GluN2B affinity of (R,R)-2 (Ki = 17 nM) indicating the importance of the phenolic OH moiety for the interaction with the receptor protein. Introduction of an additional CH3 moiety in 2-position led to a slight decrease of GluN2B affinity as can be seen by comparing the affinity data of cis-4a and 5. The homologous phenylpentyl derivative cis-4b shows the highest GluN2B affinity (Ki = 56 nM) of this series of compounds. According to docking studies cis-4a adopts the same binding mode as the cocrystallized ligand ifenprodil-keto 1A and 5 at the interface of the GluN2B and GluN1a subunits. The same crucial H-bonds are formed between the C(O)NH2 moiety of Gln110 within the GluN2B subunit and the protonated amino moiety and the OH moiety of (R,R)-cis-4a.
|
Displacement of [3H]-(+)-Pentazocine from sigma 1 receptor in guinea pig brain cortex membranes after 120 mins by scintillation counting analysis
|
Cavia porcellus
|
125.0
nM
|
|
Journal : Bioorg Med Chem
Title : 2-Methyltetrahydro-3-benzazepin-1-ols - The missing link in SAR of GluN2B selective NMDA receptor antagonists.
Year : 2018
Volume : 26
Issue : 2
First Page : 501
Last Page : 508
Authors : Dey S, Schepmann D, Wünsch B.
Abstract : The NMDA receptor containing GluN2B subunits represents a promising target for the development of drugs for the treatment of various neurological disorders including neurodegenerative diseases. In order to study the role of CH3 and OH moieties trisubstituted tetrahydro-3-benzazepines 4 were designed as missing link between tetra- and disubstituted 3-benzazepines 2 and 5. The synthesis of 4 comprises eight reaction steps starting from alanine. The intramolecular Friedel-Crafts acylation to obtain the ketone 12 and the base-catalyzed elimination of trifluoromethanesulfinate (CF3SO2-) followed by NaBH4 reduction represent the key steps. The GluN2B affinity of the cis-configured 3-benzazepin-1-ol cis-4a with a 4-phenylbutyl side chain (Ki = 252 nM) is considerably lower than the GluN2B affinity of (R,R)-2 (Ki = 17 nM) indicating the importance of the phenolic OH moiety for the interaction with the receptor protein. Introduction of an additional CH3 moiety in 2-position led to a slight decrease of GluN2B affinity as can be seen by comparing the affinity data of cis-4a and 5. The homologous phenylpentyl derivative cis-4b shows the highest GluN2B affinity (Ki = 56 nM) of this series of compounds. According to docking studies cis-4a adopts the same binding mode as the cocrystallized ligand ifenprodil-keto 1A and 5 at the interface of the GluN2B and GluN1a subunits. The same crucial H-bonds are formed between the C(O)NH2 moiety of Gln110 within the GluN2B subunit and the protonated amino moiety and the OH moiety of (R,R)-cis-4a.
|
Displacement of [3H]ifenprodil from recombinant human GluN1A/GluN2B receptor expressed in mouse L(tk-) cell membranes after 120 mins by microbeta scintillation counting method
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Deconstruction - reconstruction approach to analyze the essential structural elements of tetrahydro-3-benzazepine-based antagonists of GluN2B subunit containing NMDA receptors.
Year : 2017
Volume : 138
First Page : 552
Last Page : 564
Authors : Dey S, Temme L, Schreiber JA, Schepmann D, Frehland B, Lehmkuhl K, Strutz-Seebohm N, Seebohm G, Wünsch B.
Abstract : The role of the phenolic and benzylic OH moieties for the interaction of tetrahydro-3-benzazepine-1,7-diol 3d with GluN2B subunit containing NMDA receptors was analyzed by their stepwise removal. Elimination of trifluormethanesulfinate from 10 and 13 represent the key steps in the synthesis. Removal of phenolic OH moiety led to 5-fold reduced GluN2B affinity of 4d compared with 3d. Additional removal of the benzylic OH moiety (5d) resulted in further reduced GluN2B affinity but increased σ1 and σ2 affinities. Introduction of a NO2 (6d) or NH2 moiety (7d) decreased the GluN2B affinity. 3-Benzazepin-1-ol 4i with the N-phenylcyclohexyl side chain showed the highest GluN2B affinity of this series of compounds (Ki = 2.2 nM) and, moreover, high selectivity over the PCP binding site, σ1 and σ2 receptors. In docking studies 3-benzazepines (S)-4-7 adopt the same binding poses as ifenprodil and display the same crucial interactions. Unexpectedly, the high-affinity ligands (S)-4i, (S)-4j, and (S)-6i were not able to inhibit the glutamate/glycine evoked current in two-electrode voltage clamp measurements and the cytotoxic effects of glutamate/glycine on transfected cell lines.
|
Displacement of [3H]-(+)-pentazocine from sigma1 receptor in guinea pig brain cortex membranes after 120 mins by microbeta scintillation counting method
|
Cavia porcellus
|
125.0
nM
|
|
Journal : Eur J Med Chem
Title : Deconstruction - reconstruction approach to analyze the essential structural elements of tetrahydro-3-benzazepine-based antagonists of GluN2B subunit containing NMDA receptors.
Year : 2017
Volume : 138
First Page : 552
Last Page : 564
Authors : Dey S, Temme L, Schreiber JA, Schepmann D, Frehland B, Lehmkuhl K, Strutz-Seebohm N, Seebohm G, Wünsch B.
Abstract : The role of the phenolic and benzylic OH moieties for the interaction of tetrahydro-3-benzazepine-1,7-diol 3d with GluN2B subunit containing NMDA receptors was analyzed by their stepwise removal. Elimination of trifluormethanesulfinate from 10 and 13 represent the key steps in the synthesis. Removal of phenolic OH moiety led to 5-fold reduced GluN2B affinity of 4d compared with 3d. Additional removal of the benzylic OH moiety (5d) resulted in further reduced GluN2B affinity but increased σ1 and σ2 affinities. Introduction of a NO2 (6d) or NH2 moiety (7d) decreased the GluN2B affinity. 3-Benzazepin-1-ol 4i with the N-phenylcyclohexyl side chain showed the highest GluN2B affinity of this series of compounds (Ki = 2.2 nM) and, moreover, high selectivity over the PCP binding site, σ1 and σ2 receptors. In docking studies 3-benzazepines (S)-4-7 adopt the same binding poses as ifenprodil and display the same crucial interactions. Unexpectedly, the high-affinity ligands (S)-4i, (S)-4j, and (S)-6i were not able to inhibit the glutamate/glycine evoked current in two-electrode voltage clamp measurements and the cytotoxic effects of glutamate/glycine on transfected cell lines.
|
Displacement of [3H]DTG from sigma2 receptor in rat liver membranes after 120 mins by microbeta scintillation counting method
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : Eur J Med Chem
Title : Deconstruction - reconstruction approach to analyze the essential structural elements of tetrahydro-3-benzazepine-based antagonists of GluN2B subunit containing NMDA receptors.
Year : 2017
Volume : 138
First Page : 552
Last Page : 564
Authors : Dey S, Temme L, Schreiber JA, Schepmann D, Frehland B, Lehmkuhl K, Strutz-Seebohm N, Seebohm G, Wünsch B.
Abstract : The role of the phenolic and benzylic OH moieties for the interaction of tetrahydro-3-benzazepine-1,7-diol 3d with GluN2B subunit containing NMDA receptors was analyzed by their stepwise removal. Elimination of trifluormethanesulfinate from 10 and 13 represent the key steps in the synthesis. Removal of phenolic OH moiety led to 5-fold reduced GluN2B affinity of 4d compared with 3d. Additional removal of the benzylic OH moiety (5d) resulted in further reduced GluN2B affinity but increased σ1 and σ2 affinities. Introduction of a NO2 (6d) or NH2 moiety (7d) decreased the GluN2B affinity. 3-Benzazepin-1-ol 4i with the N-phenylcyclohexyl side chain showed the highest GluN2B affinity of this series of compounds (Ki = 2.2 nM) and, moreover, high selectivity over the PCP binding site, σ1 and σ2 receptors. In docking studies 3-benzazepines (S)-4-7 adopt the same binding poses as ifenprodil and display the same crucial interactions. Unexpectedly, the high-affinity ligands (S)-4i, (S)-4j, and (S)-6i were not able to inhibit the glutamate/glycine evoked current in two-electrode voltage clamp measurements and the cytotoxic effects of glutamate/glycine on transfected cell lines.
|
Antagonist activity at GluN1A/GluN2A receptor (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of glutamate/glycine-induced channel current at 1 uM at -70 mV holding potential by two electrode voltage clamp method relative to control
|
Homo sapiens
|
87.0
%
|
|
Journal : Eur J Med Chem
Title : Deconstruction - reconstruction approach to analyze the essential structural elements of tetrahydro-3-benzazepine-based antagonists of GluN2B subunit containing NMDA receptors.
Year : 2017
Volume : 138
First Page : 552
Last Page : 564
Authors : Dey S, Temme L, Schreiber JA, Schepmann D, Frehland B, Lehmkuhl K, Strutz-Seebohm N, Seebohm G, Wünsch B.
Abstract : The role of the phenolic and benzylic OH moieties for the interaction of tetrahydro-3-benzazepine-1,7-diol 3d with GluN2B subunit containing NMDA receptors was analyzed by their stepwise removal. Elimination of trifluormethanesulfinate from 10 and 13 represent the key steps in the synthesis. Removal of phenolic OH moiety led to 5-fold reduced GluN2B affinity of 4d compared with 3d. Additional removal of the benzylic OH moiety (5d) resulted in further reduced GluN2B affinity but increased σ1 and σ2 affinities. Introduction of a NO2 (6d) or NH2 moiety (7d) decreased the GluN2B affinity. 3-Benzazepin-1-ol 4i with the N-phenylcyclohexyl side chain showed the highest GluN2B affinity of this series of compounds (Ki = 2.2 nM) and, moreover, high selectivity over the PCP binding site, σ1 and σ2 receptors. In docking studies 3-benzazepines (S)-4-7 adopt the same binding poses as ifenprodil and display the same crucial interactions. Unexpectedly, the high-affinity ligands (S)-4i, (S)-4j, and (S)-6i were not able to inhibit the glutamate/glycine evoked current in two-electrode voltage clamp measurements and the cytotoxic effects of glutamate/glycine on transfected cell lines.
|
Displacement of [3H]Ifenprodil from GluN2B receptor (unknown origin) expressed in mouse L(tk-) cell membranes incubated for 120 mins measured for 5 mins by scintillation counting method
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Hydroxymethyl bioisosteres of phenolic GluN2B-selective NMDA receptor antagonists: Design, synthesis and pharmacological evaluation.
Year : 2018
Volume : 144
First Page : 672
Last Page : 681
Authors : Temme L, Frehland B, Schepmann D, Robaa D, Sippl W, Wünsch B.
Abstract : Antagonists addressing selectively NMDA receptors containing the GluN2B subunit are of particular interest for the treatment of various neurological disorders including neurodegenerative diseases. With the aim to bioisosterically replace the metabolically labile phenol of 7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ols, several analogs were docked into the ifenprodil binding site leading to the hydroxymethyl derivatives 4 as promising candidates. They display the same binding pose as Ro 25-6981 and the same H-bond interactions with Gln110 and Glu236 within the GluN2B subunit. The phenylalkyl moieties occupy the hydrophobic pocket formed predominantly by Pro78 (GluN2B), Phe114 (GluN2B), and Tyr109 (GluN1b). Starting from o-phthalaldehyde, the hydroxymethyl derivatives 4 were prepared in a 7-step synthesis with a haloform reaction of trichloroacetophenone 7 as key step. In receptor binding studies, the phenylpropyl derivative 4a shows promising GluN2B affinity (Ki = 101 nM) and high selectivity over the PCP binding site and both σ receptor subtypes. 4a was able to inhibit the glutamate/glycine induced cytotoxicity at mouse fibroblasts with an IC50 value of 5.2 μM. It is assumed that the hydroxymethyl moiety of 4a stabilizes the closed channel conformation by an H-bond with Glu236 as does the phenolic OH moiety of 3, Ro 25-6981 and ifenprodil.
|
Displacement of [3H]-(+)-pentazocine from sigma-1 receptor in guinea pig brain cortex membranes incubated for 120 mins measured for 5 mins by scintillation counting method
|
Cavia porcellus
|
125.0
nM
|
|
Journal : Eur J Med Chem
Title : Hydroxymethyl bioisosteres of phenolic GluN2B-selective NMDA receptor antagonists: Design, synthesis and pharmacological evaluation.
Year : 2018
Volume : 144
First Page : 672
Last Page : 681
Authors : Temme L, Frehland B, Schepmann D, Robaa D, Sippl W, Wünsch B.
Abstract : Antagonists addressing selectively NMDA receptors containing the GluN2B subunit are of particular interest for the treatment of various neurological disorders including neurodegenerative diseases. With the aim to bioisosterically replace the metabolically labile phenol of 7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ols, several analogs were docked into the ifenprodil binding site leading to the hydroxymethyl derivatives 4 as promising candidates. They display the same binding pose as Ro 25-6981 and the same H-bond interactions with Gln110 and Glu236 within the GluN2B subunit. The phenylalkyl moieties occupy the hydrophobic pocket formed predominantly by Pro78 (GluN2B), Phe114 (GluN2B), and Tyr109 (GluN1b). Starting from o-phthalaldehyde, the hydroxymethyl derivatives 4 were prepared in a 7-step synthesis with a haloform reaction of trichloroacetophenone 7 as key step. In receptor binding studies, the phenylpropyl derivative 4a shows promising GluN2B affinity (Ki = 101 nM) and high selectivity over the PCP binding site and both σ receptor subtypes. 4a was able to inhibit the glutamate/glycine induced cytotoxicity at mouse fibroblasts with an IC50 value of 5.2 μM. It is assumed that the hydroxymethyl moiety of 4a stabilizes the closed channel conformation by an H-bond with Glu236 as does the phenolic OH moiety of 3, Ro 25-6981 and ifenprodil.
|
Displacement of [3H]-di-o-tolylguanidine from sigma-2 receptor in rat liver membranes incubated for 120 mins measured for 5 mins by scintillation counting method
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : Eur J Med Chem
Title : Hydroxymethyl bioisosteres of phenolic GluN2B-selective NMDA receptor antagonists: Design, synthesis and pharmacological evaluation.
Year : 2018
Volume : 144
First Page : 672
Last Page : 681
Authors : Temme L, Frehland B, Schepmann D, Robaa D, Sippl W, Wünsch B.
Abstract : Antagonists addressing selectively NMDA receptors containing the GluN2B subunit are of particular interest for the treatment of various neurological disorders including neurodegenerative diseases. With the aim to bioisosterically replace the metabolically labile phenol of 7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ols, several analogs were docked into the ifenprodil binding site leading to the hydroxymethyl derivatives 4 as promising candidates. They display the same binding pose as Ro 25-6981 and the same H-bond interactions with Gln110 and Glu236 within the GluN2B subunit. The phenylalkyl moieties occupy the hydrophobic pocket formed predominantly by Pro78 (GluN2B), Phe114 (GluN2B), and Tyr109 (GluN1b). Starting from o-phthalaldehyde, the hydroxymethyl derivatives 4 were prepared in a 7-step synthesis with a haloform reaction of trichloroacetophenone 7 as key step. In receptor binding studies, the phenylpropyl derivative 4a shows promising GluN2B affinity (Ki = 101 nM) and high selectivity over the PCP binding site and both σ receptor subtypes. 4a was able to inhibit the glutamate/glycine induced cytotoxicity at mouse fibroblasts with an IC50 value of 5.2 μM. It is assumed that the hydroxymethyl moiety of 4a stabilizes the closed channel conformation by an H-bond with Glu236 as does the phenolic OH moiety of 3, Ro 25-6981 and ifenprodil.
|
Antagonist activity at GluN2B/GluN1a receptor (unknown origin) expressed in mouse L(tk-) cells assessed as cytoprotection against glycine/(S)-glutamate-induced cell death preincubated for 30 mins followed by glycine/(S)-glutamate addition measured after 6 hrs by LDH assay
|
Homo sapiens
|
590.0
nM
|
|
Journal : Eur J Med Chem
Title : Hydroxymethyl bioisosteres of phenolic GluN2B-selective NMDA receptor antagonists: Design, synthesis and pharmacological evaluation.
Year : 2018
Volume : 144
First Page : 672
Last Page : 681
Authors : Temme L, Frehland B, Schepmann D, Robaa D, Sippl W, Wünsch B.
Abstract : Antagonists addressing selectively NMDA receptors containing the GluN2B subunit are of particular interest for the treatment of various neurological disorders including neurodegenerative diseases. With the aim to bioisosterically replace the metabolically labile phenol of 7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ols, several analogs were docked into the ifenprodil binding site leading to the hydroxymethyl derivatives 4 as promising candidates. They display the same binding pose as Ro 25-6981 and the same H-bond interactions with Gln110 and Glu236 within the GluN2B subunit. The phenylalkyl moieties occupy the hydrophobic pocket formed predominantly by Pro78 (GluN2B), Phe114 (GluN2B), and Tyr109 (GluN1b). Starting from o-phthalaldehyde, the hydroxymethyl derivatives 4 were prepared in a 7-step synthesis with a haloform reaction of trichloroacetophenone 7 as key step. In receptor binding studies, the phenylpropyl derivative 4a shows promising GluN2B affinity (Ki = 101 nM) and high selectivity over the PCP binding site and both σ receptor subtypes. 4a was able to inhibit the glutamate/glycine induced cytotoxicity at mouse fibroblasts with an IC50 value of 5.2 μM. It is assumed that the hydroxymethyl moiety of 4a stabilizes the closed channel conformation by an H-bond with Glu236 as does the phenolic OH moiety of 3, Ro 25-6981 and ifenprodil.
|
Displacement of [3H]-ifenprodil from GluN2B receptor (unknown origin) expressed in mouse L (tk-) cell membranes after 120 mins by scintillation counting method
|
Homo sapiens
|
10.0
nM
|
|
Journal : MedChemComm
Title : Do GluN2B subunit containing NMDA receptors tolerate a fluorine atom in the phenylalkyl side chain?
Year : 2017
Volume : 8
Issue : 5
First Page : 975
Last Page : 981
Authors : Shuto Y, Thum S, Temme L, Schepmann D, Kitamura M, Wünsch B.
Abstract : The influence of an F-atom in the side chain of benzo[7]annulen-7-amines on the affinity towards GluN2B subunit containing NMDA receptors and the selectivity over related receptors was investigated. The synthesis of <b>5a</b> and <b>5b</b> was performed by reductive amination of the ketone <b>6</b> with primary alkanamines <b>14a</b> and <b>14b</b> bearing an F-atom in β-position. The GluN2B affinities of non-fluorinated and fluorinated ligands <b>4</b> and <b>5</b> are almost identical. The low impact of the F-atom on GluN2B affinity was unexpected, as it influences several chemical and physicochemical properties of the ligands. However, introduction of the F-atom led to reduced selectivity over <i>σ</i> receptors. Whereas <b>5a</b> and <b>5b</b> display still a 2-3-fold preference for GluN2B over <i>σ</i><sub>1</sub> receptors, they show almost the same affinity to GluN2B and <i>σ</i><sub>2</sub> receptors.
|
Displacement of [3H]-di-o-tolylguanidine from sigma 2 receptor in rat liver membranes after 120 mins by scintillation counting analysis
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : MedChemComm
Title : Do GluN2B subunit containing NMDA receptors tolerate a fluorine atom in the phenylalkyl side chain?
Year : 2017
Volume : 8
Issue : 5
First Page : 975
Last Page : 981
Authors : Shuto Y, Thum S, Temme L, Schepmann D, Kitamura M, Wünsch B.
Abstract : The influence of an F-atom in the side chain of benzo[7]annulen-7-amines on the affinity towards GluN2B subunit containing NMDA receptors and the selectivity over related receptors was investigated. The synthesis of <b>5a</b> and <b>5b</b> was performed by reductive amination of the ketone <b>6</b> with primary alkanamines <b>14a</b> and <b>14b</b> bearing an F-atom in β-position. The GluN2B affinities of non-fluorinated and fluorinated ligands <b>4</b> and <b>5</b> are almost identical. The low impact of the F-atom on GluN2B affinity was unexpected, as it influences several chemical and physicochemical properties of the ligands. However, introduction of the F-atom led to reduced selectivity over <i>σ</i> receptors. Whereas <b>5a</b> and <b>5b</b> display still a 2-3-fold preference for GluN2B over <i>σ</i><sub>1</sub> receptors, they show almost the same affinity to GluN2B and <i>σ</i><sub>2</sub> receptors.
|
Displacement of [3H](+)-Pentazocine from sigma 1 receptor in guinea pig brain membranes after 120 mins by scintillation counting analysis
|
Cavia porcellus
|
125.0
nM
|
|
Journal : MedChemComm
Title : Do GluN2B subunit containing NMDA receptors tolerate a fluorine atom in the phenylalkyl side chain?
Year : 2017
Volume : 8
Issue : 5
First Page : 975
Last Page : 981
Authors : Shuto Y, Thum S, Temme L, Schepmann D, Kitamura M, Wünsch B.
Abstract : The influence of an F-atom in the side chain of benzo[7]annulen-7-amines on the affinity towards GluN2B subunit containing NMDA receptors and the selectivity over related receptors was investigated. The synthesis of <b>5a</b> and <b>5b</b> was performed by reductive amination of the ketone <b>6</b> with primary alkanamines <b>14a</b> and <b>14b</b> bearing an F-atom in β-position. The GluN2B affinities of non-fluorinated and fluorinated ligands <b>4</b> and <b>5</b> are almost identical. The low impact of the F-atom on GluN2B affinity was unexpected, as it influences several chemical and physicochemical properties of the ligands. However, introduction of the F-atom led to reduced selectivity over <i>σ</i> receptors. Whereas <b>5a</b> and <b>5b</b> display still a 2-3-fold preference for GluN2B over <i>σ</i><sub>1</sub> receptors, they show almost the same affinity to GluN2B and <i>σ</i><sub>2</sub> receptors.
|
Displacement of [3H](+)-pentazocine from S1R in guinea pig brain cortex membranes after 120 mins by scintillation counting assay
|
Cavia porcellus
|
125.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification of dual Sigma1 receptor modulators/acetylcholinesterase inhibitors with antioxidant and neurotrophic properties, as neuroprotective agents.
Year : 2018
Volume : 158
First Page : 353
Last Page : 370
Authors : Rui M, Rossino G, Coniglio S, Monteleone S, Scuteri A, Malacrida A, Rossi D, Catenacci L, Sorrenti M, Paolillo M, Curti D, Venturini L, Schepmann D, Wünsch B, Liedl KR, Cavaletti G, Pace V, Urban E, Collina S.
Abstract : In this manuscript we report on the design, synthesis and evaluation of dual Sigma 1 Receptor (S1R) modulators/Acetylcholinesterase (AChE) inhibitors endowed with antioxidant and neurotrophic properties, potentially able to counteract neurodegeneration. The compounds based on arylalkylaminoketone scaffold integrate the pharmacophoric elements of RRC-33, a S1R modulator developed by us, donepezil, a well-known AChE inhibitor, and curcumin, a natural antioxidant compound with neuroprotective properties. A small library of compounds was synthesized and preliminary in vitro screening performed. Some compounds showed good S1R binding affinity, selectivity towards S2R and N-Methyl-d-Aspartate (NMDA) receptor, AChE relevant inhibiting activity and are potentially able to bypass the BBB, as predicted by the in silico study. For the hits 10 and 20, the antioxidant profile was assessed in SH-SY5Y human neuroblastoma cell lines by evaluating their protective effect against H2O2 cytotoxicity and reactive oxygen species (ROS) production. Tested compounds resulted effective in decreasing ROS production, thus ameliorating the cellular survival. Moreover, compounds 10 and 20 showed to be effective in promoting the neurite elongation of Dorsal Root Ganglia (DRG), thus demonstrating a promising neurotrophic activity. Of note, the tested compounds did not show any cytotoxic effect at the concentration assayed. Relying on these encouraging results, both compounds will undergo a structure optimization program for the development of therapeutic candidates for neurodegenerative diseases treatment.
|
Displacement of [3H]-DTG from S2R in rat liver membranes after 120 mins by scintillation counting assay
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification of dual Sigma1 receptor modulators/acetylcholinesterase inhibitors with antioxidant and neurotrophic properties, as neuroprotective agents.
Year : 2018
Volume : 158
First Page : 353
Last Page : 370
Authors : Rui M, Rossino G, Coniglio S, Monteleone S, Scuteri A, Malacrida A, Rossi D, Catenacci L, Sorrenti M, Paolillo M, Curti D, Venturini L, Schepmann D, Wünsch B, Liedl KR, Cavaletti G, Pace V, Urban E, Collina S.
Abstract : In this manuscript we report on the design, synthesis and evaluation of dual Sigma 1 Receptor (S1R) modulators/Acetylcholinesterase (AChE) inhibitors endowed with antioxidant and neurotrophic properties, potentially able to counteract neurodegeneration. The compounds based on arylalkylaminoketone scaffold integrate the pharmacophoric elements of RRC-33, a S1R modulator developed by us, donepezil, a well-known AChE inhibitor, and curcumin, a natural antioxidant compound with neuroprotective properties. A small library of compounds was synthesized and preliminary in vitro screening performed. Some compounds showed good S1R binding affinity, selectivity towards S2R and N-Methyl-d-Aspartate (NMDA) receptor, AChE relevant inhibiting activity and are potentially able to bypass the BBB, as predicted by the in silico study. For the hits 10 and 20, the antioxidant profile was assessed in SH-SY5Y human neuroblastoma cell lines by evaluating their protective effect against H2O2 cytotoxicity and reactive oxygen species (ROS) production. Tested compounds resulted effective in decreasing ROS production, thus ameliorating the cellular survival. Moreover, compounds 10 and 20 showed to be effective in promoting the neurite elongation of Dorsal Root Ganglia (DRG), thus demonstrating a promising neurotrophic activity. Of note, the tested compounds did not show any cytotoxic effect at the concentration assayed. Relying on these encouraging results, both compounds will undergo a structure optimization program for the development of therapeutic candidates for neurodegenerative diseases treatment.
|
Displacement of [3H]-ifenprodil from GluN1a/GluN2B (unknown origin) expressed in mouse L(tk-) cell membranes after 120 mins by scintillation counting analysis
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Identification of dual Sigma1 receptor modulators/acetylcholinesterase inhibitors with antioxidant and neurotrophic properties, as neuroprotective agents.
Year : 2018
Volume : 158
First Page : 353
Last Page : 370
Authors : Rui M, Rossino G, Coniglio S, Monteleone S, Scuteri A, Malacrida A, Rossi D, Catenacci L, Sorrenti M, Paolillo M, Curti D, Venturini L, Schepmann D, Wünsch B, Liedl KR, Cavaletti G, Pace V, Urban E, Collina S.
Abstract : In this manuscript we report on the design, synthesis and evaluation of dual Sigma 1 Receptor (S1R) modulators/Acetylcholinesterase (AChE) inhibitors endowed with antioxidant and neurotrophic properties, potentially able to counteract neurodegeneration. The compounds based on arylalkylaminoketone scaffold integrate the pharmacophoric elements of RRC-33, a S1R modulator developed by us, donepezil, a well-known AChE inhibitor, and curcumin, a natural antioxidant compound with neuroprotective properties. A small library of compounds was synthesized and preliminary in vitro screening performed. Some compounds showed good S1R binding affinity, selectivity towards S2R and N-Methyl-d-Aspartate (NMDA) receptor, AChE relevant inhibiting activity and are potentially able to bypass the BBB, as predicted by the in silico study. For the hits 10 and 20, the antioxidant profile was assessed in SH-SY5Y human neuroblastoma cell lines by evaluating their protective effect against H2O2 cytotoxicity and reactive oxygen species (ROS) production. Tested compounds resulted effective in decreasing ROS production, thus ameliorating the cellular survival. Moreover, compounds 10 and 20 showed to be effective in promoting the neurite elongation of Dorsal Root Ganglia (DRG), thus demonstrating a promising neurotrophic activity. Of note, the tested compounds did not show any cytotoxic effect at the concentration assayed. Relying on these encouraging results, both compounds will undergo a structure optimization program for the development of therapeutic candidates for neurodegenerative diseases treatment.
|
Displacement of [3H]-ifenprodil from GluN1a/GluN2B (unknown origin) expressed in L(tk-) cell membranes after 120 mins by scintillation counting analysis
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Pyridine bioisosteres of potent GluN2B subunit containing NMDA receptor antagonists with benzo[7]annulene scaffold.
Year : 2018
Volume : 157
First Page : 397
Last Page : 404
Authors : Zscherp R, Baumeister S, Schepmann D, Wünsch B.
Abstract : It has been reported that benzo [7]annulen-7-amines bearing electron withdrawing substituents such as 3d with a 2-Cl or 3e with a 2-NO2 moiety show very high affinity towards the ifenprodil binding site of GluN2B subunit containing NMDA receptors. Therefore, bioisosteres of 3 with an electron deficient pyridine ring instead of the chloro- or nitrobenzene ring were envisaged. Starting from pyridine-2,3-dicarboxylic acid (5) a five-step synthesis of the key intermediate, the ketone 10, was developed. Reductive amination with various primary amines and NaBH(OAc)3 led to the homologous secondary amines 11a-c. Subsequent methylation yielded the tertiary amines 12b and 12c. Receptor binding studies with [3H]ifenprodil revealed Ki-values above 100 nM for the most active phenylpropyl- and phenylbutylamines 11b and 11c. The >100-fold reduced GluN2B affinity of pyridines 11b and 11c compared to the GluN2B affinity of the corresponding chloro- and nitrobenzene derivatives 3d and 3e indicates that the pyridine ring is not tolerated as bioisosteric replacement of the chloro- or nitrobenzene ring in this type of compounds.
|
Displacement of [3H]-(+)-pentazocine from sigma1 receptor in guinea pig brain cortex membrane after 120 mins by scintillation counting method
|
Cavia porcellus
|
125.0
nM
|
|
Journal : Eur J Med Chem
Title : Pyridine bioisosteres of potent GluN2B subunit containing NMDA receptor antagonists with benzo[7]annulene scaffold.
Year : 2018
Volume : 157
First Page : 397
Last Page : 404
Authors : Zscherp R, Baumeister S, Schepmann D, Wünsch B.
Abstract : It has been reported that benzo [7]annulen-7-amines bearing electron withdrawing substituents such as 3d with a 2-Cl or 3e with a 2-NO2 moiety show very high affinity towards the ifenprodil binding site of GluN2B subunit containing NMDA receptors. Therefore, bioisosteres of 3 with an electron deficient pyridine ring instead of the chloro- or nitrobenzene ring were envisaged. Starting from pyridine-2,3-dicarboxylic acid (5) a five-step synthesis of the key intermediate, the ketone 10, was developed. Reductive amination with various primary amines and NaBH(OAc)3 led to the homologous secondary amines 11a-c. Subsequent methylation yielded the tertiary amines 12b and 12c. Receptor binding studies with [3H]ifenprodil revealed Ki-values above 100 nM for the most active phenylpropyl- and phenylbutylamines 11b and 11c. The >100-fold reduced GluN2B affinity of pyridines 11b and 11c compared to the GluN2B affinity of the corresponding chloro- and nitrobenzene derivatives 3d and 3e indicates that the pyridine ring is not tolerated as bioisosteric replacement of the chloro- or nitrobenzene ring in this type of compounds.
|
Displacement of [3H]-di-o-tolylguanidine from sigma2 receptor in rat liver membranes incubated for 120 mins by scintillation counting method
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : Eur J Med Chem
Title : Pyridine bioisosteres of potent GluN2B subunit containing NMDA receptor antagonists with benzo[7]annulene scaffold.
Year : 2018
Volume : 157
First Page : 397
Last Page : 404
Authors : Zscherp R, Baumeister S, Schepmann D, Wünsch B.
Abstract : It has been reported that benzo [7]annulen-7-amines bearing electron withdrawing substituents such as 3d with a 2-Cl or 3e with a 2-NO2 moiety show very high affinity towards the ifenprodil binding site of GluN2B subunit containing NMDA receptors. Therefore, bioisosteres of 3 with an electron deficient pyridine ring instead of the chloro- or nitrobenzene ring were envisaged. Starting from pyridine-2,3-dicarboxylic acid (5) a five-step synthesis of the key intermediate, the ketone 10, was developed. Reductive amination with various primary amines and NaBH(OAc)3 led to the homologous secondary amines 11a-c. Subsequent methylation yielded the tertiary amines 12b and 12c. Receptor binding studies with [3H]ifenprodil revealed Ki-values above 100 nM for the most active phenylpropyl- and phenylbutylamines 11b and 11c. The >100-fold reduced GluN2B affinity of pyridines 11b and 11c compared to the GluN2B affinity of the corresponding chloro- and nitrobenzene derivatives 3d and 3e indicates that the pyridine ring is not tolerated as bioisosteric replacement of the chloro- or nitrobenzene ring in this type of compounds.
|
Negative allosteric modulation of human GluN2B receptor expressed in xenopus laevis oocytes assessed as reduction in 3 uM glycine-induced channel current at -40 mV holding potential by two electrode voltage clamp method
|
Homo sapiens
|
110.0
nM
|
|
Journal : J Med Chem
Title : Positive and Negative Allosteric Modulators of N-Methyl-d-aspartate (NMDA) Receptors: Structure-Activity Relationships and Mechanisms of Action.
Year : 2018
Volume : 62
Issue : 1
First Page : 3
Last Page : 23
Authors : Burnell ES, Irvine M, Fang G, Sapkota K, Jane DE, Monaghan DT.
Abstract : Excitatory activity in the CNS is predominately mediated by l-glutamate through several families of l-glutamate neurotransmitter receptors. Of these, the N-methyl-d-aspartate receptor (NMDAR) family has many critical roles in CNS function and in various neuropathological and psychiatric conditions. Until recently, the types of compounds available to regulate NMDAR function have been quite limited in terms of mechanism of action, subtype selectivity, and biological effect. However, several new classes of NMDAR agents have now been identified that are positive or negative allosteric modulators (PAMs and NAMs, respectively) with various patterns of NMDAR subtype selectivity. These new agents act at several newly recognized binding sites on the NMDAR complex and offer significantly greater pharmacological control over NMDAR activity than previously available agents. The purpose of this review is to summarize the structure-activity relationships for these new NMDAR modulator drug classes and to describe the current understanding of their mechanisms of action.
|
Displacement of [3H]ifenprodil from GluN1A/GluN2B (unknown origin) expressed in mouse L(tk-) cell membranes after 120 mins by solid scintillation counting method
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg Med Chem
Title : Impact of hydroxy moieties at the benzo[7]annulene ring system of GluN2B ligands: Design, synthesis and biological evaluation.
Year : 2019
Volume : 27
Issue : 23
First Page : 115146
Last Page : 115146
Authors : Temme L, Börgel F, Schepmann D, Robaa D, Sippl W, Daniliuc C, Wünsch B.
Abstract : In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11-13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc)2, HCO2H, phosphane ligand) or the 6-hydroxyketone 10 (H2, Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc)3 afforded the benzo[7]annulenamines 11-13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of Ki = 49 nM and a cytoprotective activity of IC50 = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CH2OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition.
|
Displacement of [3H]-(+)-pentazocine from sigma1 receptor in guinea pig brain cortex membranes incubated for 120 mins by solid scintillation counting method
|
Cavia porcellus
|
125.0
nM
|
|
Journal : Bioorg Med Chem
Title : Impact of hydroxy moieties at the benzo[7]annulene ring system of GluN2B ligands: Design, synthesis and biological evaluation.
Year : 2019
Volume : 27
Issue : 23
First Page : 115146
Last Page : 115146
Authors : Temme L, Börgel F, Schepmann D, Robaa D, Sippl W, Daniliuc C, Wünsch B.
Abstract : In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11-13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc)2, HCO2H, phosphane ligand) or the 6-hydroxyketone 10 (H2, Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc)3 afforded the benzo[7]annulenamines 11-13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of Ki = 49 nM and a cytoprotective activity of IC50 = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CH2OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition.
|
Displacement of [3H]di-o-tolylguanidine from sigma2 receptor in rat liver membranes measured after 120 mins by solid scintillation counting method
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : Bioorg Med Chem
Title : Impact of hydroxy moieties at the benzo[7]annulene ring system of GluN2B ligands: Design, synthesis and biological evaluation.
Year : 2019
Volume : 27
Issue : 23
First Page : 115146
Last Page : 115146
Authors : Temme L, Börgel F, Schepmann D, Robaa D, Sippl W, Daniliuc C, Wünsch B.
Abstract : In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11-13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc)2, HCO2H, phosphane ligand) or the 6-hydroxyketone 10 (H2, Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc)3 afforded the benzo[7]annulenamines 11-13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of Ki = 49 nM and a cytoprotective activity of IC50 = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CH2OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition.
|
Cytoprotection against glutamate/glycine-induced cytotoxicity against mouse LTK cells expressing GluN1a/GluN2B preincubated 30 mins followed by glutamate/glycine addition and measured after 6 hrs by LDH assay
|
Mus musculus
|
250.0
nM
|
|
Journal : Bioorg Med Chem
Title : Impact of hydroxy moieties at the benzo[7]annulene ring system of GluN2B ligands: Design, synthesis and biological evaluation.
Year : 2019
Volume : 27
Issue : 23
First Page : 115146
Last Page : 115146
Authors : Temme L, Börgel F, Schepmann D, Robaa D, Sippl W, Daniliuc C, Wünsch B.
Abstract : In this study, the impact of one or two hydroxy moieties at the benzo[7]annulene scaffold on the GluN2B affinity and cytoprotective activity was analyzed. The key intermediate for the synthesis of OH-substituted benzo[7]annulenamines 11-13 and 17 was the epoxyketone 8. Reductive epoxide opening of 8 resulted with high regioselectivity in the 5-hydroxyketone 9 (Pd(OAc)2, HCO2H, phosphane ligand) or the 6-hydroxyketone 10 (H2, Pd/C), whereas hydrolysis in aqueous dioxane led to the dihydroxyketone 14. Reductive amination of these ketones with primary amines and NaBH(OAc)3 afforded the benzo[7]annulenamines 11-13 and 17. In receptor binding studies 5-OH derivatives 11 and 12 showed higher GluN2B affinity than 6-OH derivatives 13, which in turn were more active than 5,6-di-OH derivative 17a. The same order was found for the cytoprotective activity of the ligands. The tertiary amine 12a with one OH moiety in 5-position represents the most promising GluN2B negative allosteric modulator with a binding affinity of Ki = 49 nM and a cytoprotective activity of IC50 = 580 nM. In the binding pocket 12a shows a crucial H-bond between the benzylic OH moiety and the backbone carbonyl O-atom of Ser132 (GluN1b). It was concluded that a 5-OH moiety is essential for the inhibition of the NMDA receptor associated ion channel, whereas a OH moiety in 6-position is detrimental for binding and inhibition. An OH or CH2OH moiety at 2-position results in binding at the ifenprodil binding site, but very weak ion channel inhibition.
|
Displacement of [3H]-ifenprodil from GluN2B (unknown origin) expressed in rat L(tk) cells measured after 120 mins by scintillation counting analysis
|
Homo sapiens
|
10.0
nM
|
|
Journal : MedChemComm
Title : Synthesis and receptor binding of thiophene bioisosteres of potent GluN2B ligands with a benzo[7]annulene-scaffold.
Year : 2019
Volume : 10
Issue : 2
First Page : 315
Last Page : 325
Authors : Baumeister S, Schepmann D, Wünsch B.
Abstract : The involvement of NMDA receptors containing the GluN2B subunit in neurodegenerative disorders including Alzheimer's and Parkinson's disease renders this NMDA receptor subtype an interesting pharmacological target. The aim of this study was the bioisosteric replacement of benzene, methoxybenzene and aniline moieties of known potent GluN2B selective NMDA receptor antagonists by a thiophene ring. In a nine-step synthesis starting from commercially available propionic acid <b>9</b> the thiophene derivative <b>7a</b> was obtained as a bioisostere of the potent GluN2B ligands <i>cis</i>-<b>3</b> and <i>trans</i>-<b>3</b>. [7]Annuleno[<i>b</i>]thiophene <b>8a</b> without a benzylic OH moiety was prepared in a six-step synthesis starting from carboxylic acid <b>18</b>. <b>8a</b> represents a bioisostere of potent GluN2B ligands <b>4</b> and <b>5</b>. [7]Annulenothiophene <b>8a</b> without a benzylic OH moiety reveals approx. 8-fold higher GluN2B affinity (<i>K</i> <sub>i</sub> = 26 nM) than the analogous thiophene derivative <b>7a</b> with a benzylic OH moiety (<i>K</i> <sub>i</sub> = 204 nM). Both thiophene bioisosteres show a slight preference for GluN2B receptors over both σ receptors. The data indicate that the bioisosteric replacement of benzene or substituted benzene rings by a thiophene ring is well tolerated by the NMDA receptor. Furthermore, the benzylic OH moiety seems not to be essential for high GluN2B affinity.
|
Displacement of [3H]-(+)-pentazocine from sigma1 receptor in guinea pig brain cortex membranes measured after 120 mins by scintillation counting analysis
|
Cavia porcellus
|
125.0
nM
|
|
Journal : MedChemComm
Title : Synthesis and receptor binding of thiophene bioisosteres of potent GluN2B ligands with a benzo[7]annulene-scaffold.
Year : 2019
Volume : 10
Issue : 2
First Page : 315
Last Page : 325
Authors : Baumeister S, Schepmann D, Wünsch B.
Abstract : The involvement of NMDA receptors containing the GluN2B subunit in neurodegenerative disorders including Alzheimer's and Parkinson's disease renders this NMDA receptor subtype an interesting pharmacological target. The aim of this study was the bioisosteric replacement of benzene, methoxybenzene and aniline moieties of known potent GluN2B selective NMDA receptor antagonists by a thiophene ring. In a nine-step synthesis starting from commercially available propionic acid <b>9</b> the thiophene derivative <b>7a</b> was obtained as a bioisostere of the potent GluN2B ligands <i>cis</i>-<b>3</b> and <i>trans</i>-<b>3</b>. [7]Annuleno[<i>b</i>]thiophene <b>8a</b> without a benzylic OH moiety was prepared in a six-step synthesis starting from carboxylic acid <b>18</b>. <b>8a</b> represents a bioisostere of potent GluN2B ligands <b>4</b> and <b>5</b>. [7]Annulenothiophene <b>8a</b> without a benzylic OH moiety reveals approx. 8-fold higher GluN2B affinity (<i>K</i> <sub>i</sub> = 26 nM) than the analogous thiophene derivative <b>7a</b> with a benzylic OH moiety (<i>K</i> <sub>i</sub> = 204 nM). Both thiophene bioisosteres show a slight preference for GluN2B receptors over both σ receptors. The data indicate that the bioisosteric replacement of benzene or substituted benzene rings by a thiophene ring is well tolerated by the NMDA receptor. Furthermore, the benzylic OH moiety seems not to be essential for high GluN2B affinity.
|
Displacement of [3H]di-o-tolylguanidine from sigma2 receptor in rat liver membranes measured after 120 mins by scintillation counting analysis
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : MedChemComm
Title : Synthesis and receptor binding of thiophene bioisosteres of potent GluN2B ligands with a benzo[7]annulene-scaffold.
Year : 2019
Volume : 10
Issue : 2
First Page : 315
Last Page : 325
Authors : Baumeister S, Schepmann D, Wünsch B.
Abstract : The involvement of NMDA receptors containing the GluN2B subunit in neurodegenerative disorders including Alzheimer's and Parkinson's disease renders this NMDA receptor subtype an interesting pharmacological target. The aim of this study was the bioisosteric replacement of benzene, methoxybenzene and aniline moieties of known potent GluN2B selective NMDA receptor antagonists by a thiophene ring. In a nine-step synthesis starting from commercially available propionic acid <b>9</b> the thiophene derivative <b>7a</b> was obtained as a bioisostere of the potent GluN2B ligands <i>cis</i>-<b>3</b> and <i>trans</i>-<b>3</b>. [7]Annuleno[<i>b</i>]thiophene <b>8a</b> without a benzylic OH moiety was prepared in a six-step synthesis starting from carboxylic acid <b>18</b>. <b>8a</b> represents a bioisostere of potent GluN2B ligands <b>4</b> and <b>5</b>. [7]Annulenothiophene <b>8a</b> without a benzylic OH moiety reveals approx. 8-fold higher GluN2B affinity (<i>K</i> <sub>i</sub> = 26 nM) than the analogous thiophene derivative <b>7a</b> with a benzylic OH moiety (<i>K</i> <sub>i</sub> = 204 nM). Both thiophene bioisosteres show a slight preference for GluN2B receptors over both σ receptors. The data indicate that the bioisosteric replacement of benzene or substituted benzene rings by a thiophene ring is well tolerated by the NMDA receptor. Furthermore, the benzylic OH moiety seems not to be essential for high GluN2B affinity.
|
Displacement of [3H]-ifenprodil from GluN2B (unknown origin) expressed in mouse L(tk) cells after 120 mins by MicroBeta scintillation counting analysis
|
Homo sapiens
|
13.3
nM
|
|
Journal : MedChemComm
Title : Synthesis and receptor binding of thiophene bioisosteres of potent GluN2B ligands with a benzo[7]annulene-scaffold.
Year : 2019
Volume : 10
Issue : 2
First Page : 315
Last Page : 325
Authors : Baumeister S, Schepmann D, Wünsch B.
Abstract : The involvement of NMDA receptors containing the GluN2B subunit in neurodegenerative disorders including Alzheimer's and Parkinson's disease renders this NMDA receptor subtype an interesting pharmacological target. The aim of this study was the bioisosteric replacement of benzene, methoxybenzene and aniline moieties of known potent GluN2B selective NMDA receptor antagonists by a thiophene ring. In a nine-step synthesis starting from commercially available propionic acid <b>9</b> the thiophene derivative <b>7a</b> was obtained as a bioisostere of the potent GluN2B ligands <i>cis</i>-<b>3</b> and <i>trans</i>-<b>3</b>. [7]Annuleno[<i>b</i>]thiophene <b>8a</b> without a benzylic OH moiety was prepared in a six-step synthesis starting from carboxylic acid <b>18</b>. <b>8a</b> represents a bioisostere of potent GluN2B ligands <b>4</b> and <b>5</b>. [7]Annulenothiophene <b>8a</b> without a benzylic OH moiety reveals approx. 8-fold higher GluN2B affinity (<i>K</i> <sub>i</sub> = 26 nM) than the analogous thiophene derivative <b>7a</b> with a benzylic OH moiety (<i>K</i> <sub>i</sub> = 204 nM). Both thiophene bioisosteres show a slight preference for GluN2B receptors over both σ receptors. The data indicate that the bioisosteric replacement of benzene or substituted benzene rings by a thiophene ring is well tolerated by the NMDA receptor. Furthermore, the benzylic OH moiety seems not to be essential for high GluN2B affinity.
|
Displacement of [3H]ifenprodil from human recombinant GluN2B expressed in mouse L(tk-) cell membranes co-expressing GluN1a incubated for 120 mins by scintillation counting method
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg Med Chem
Title : Thiophene bioisosteres of GluN2B selective NMDA receptor antagonists: Synthesis and pharmacological evaluation of [7]annuleno[b]thiophen-6-amines.
Year : 2020
Volume : 28
Issue : 2
First Page : 115245
Last Page : 115245
Authors : Baumeister S, Schepmann D, Wünsch B.
Abstract : Thiophene bioisosteres of potent GluN2B receptor negative allosteric modulators were prepared and evaluated pharmacologically. The five-step synthesis of 4,5,7,8-tetrahydro[7]annuleno[b]thiophen-6-one (10) was considerably improved by carboxylation of thiophene-3-carboxylic acid (8) in the first reaction step. Reductive amination and alkylation led to three homologous series of secondary and tertiary phenylalkylamines 5, 11 and 12. Metalation, reaction with 1-formylpiperidine and subsequent reduction provided hydroxymethyl derivatives 15 and 16, which had been designed as bioisosteres of phenols. 2-Bromo derivatives 18 were obtained by bromination of ketone 10 with NBS and subsequent reductive amination. High GluN2B affinity was achieved with [7]annuleno[b]thiophenes bearing a 3-phenylpropylamino or 4-phenylbutylamino moiety (e.g. 5c: K<sub>i</sub> = 5.9 nM; 11d: K<sub>i</sub> = 9.0 nM). Tertiary ethylamines 12 showed lower GluN2B affinity than tertiary methylamines 11 or secondary amines 5 (e.g. 5c: K<sub>i</sub> = 5.9 nM; 11c: K<sub>i</sub> = 6.0; 12c: K<sub>i</sub> = 51 nM). A Br-atom or a hydroxymethyl moiety in 2-position were less tolerated by the GluN2B receptor. Very similar relationships between the structure and GluN2B affinity and structure and σ affinity, in particular σ<sub>2</sub> affinity, were detected. A slight preference for the ifenprodil binding site of GluN2B receptors over σ<sub>1</sub> and σ<sub>2</sub> receptors was found for methylamines 11c (≈2-fold) and 11d (≈1.5-2-fold) as well as for bromo derivative 18c (≈3-fold).
|
Displacement of [3H]-(+)-pentazocine from sigma1 receptor in guinea pig brain membranes incubated for 120 mins by scintillation counting method
|
Cavia porcellus
|
125.0
nM
|
|
Journal : Bioorg Med Chem
Title : Thiophene bioisosteres of GluN2B selective NMDA receptor antagonists: Synthesis and pharmacological evaluation of [7]annuleno[b]thiophen-6-amines.
Year : 2020
Volume : 28
Issue : 2
First Page : 115245
Last Page : 115245
Authors : Baumeister S, Schepmann D, Wünsch B.
Abstract : Thiophene bioisosteres of potent GluN2B receptor negative allosteric modulators were prepared and evaluated pharmacologically. The five-step synthesis of 4,5,7,8-tetrahydro[7]annuleno[b]thiophen-6-one (10) was considerably improved by carboxylation of thiophene-3-carboxylic acid (8) in the first reaction step. Reductive amination and alkylation led to three homologous series of secondary and tertiary phenylalkylamines 5, 11 and 12. Metalation, reaction with 1-formylpiperidine and subsequent reduction provided hydroxymethyl derivatives 15 and 16, which had been designed as bioisosteres of phenols. 2-Bromo derivatives 18 were obtained by bromination of ketone 10 with NBS and subsequent reductive amination. High GluN2B affinity was achieved with [7]annuleno[b]thiophenes bearing a 3-phenylpropylamino or 4-phenylbutylamino moiety (e.g. 5c: K<sub>i</sub> = 5.9 nM; 11d: K<sub>i</sub> = 9.0 nM). Tertiary ethylamines 12 showed lower GluN2B affinity than tertiary methylamines 11 or secondary amines 5 (e.g. 5c: K<sub>i</sub> = 5.9 nM; 11c: K<sub>i</sub> = 6.0; 12c: K<sub>i</sub> = 51 nM). A Br-atom or a hydroxymethyl moiety in 2-position were less tolerated by the GluN2B receptor. Very similar relationships between the structure and GluN2B affinity and structure and σ affinity, in particular σ<sub>2</sub> affinity, were detected. A slight preference for the ifenprodil binding site of GluN2B receptors over σ<sub>1</sub> and σ<sub>2</sub> receptors was found for methylamines 11c (≈2-fold) and 11d (≈1.5-2-fold) as well as for bromo derivative 18c (≈3-fold).
|
Displacement of [3H]-di-o-tolylguanidine from sigma2 receptor in rat liver membranes incubated for 120 mins in the presence of sigma1 receptor ligand (+)-pentazocine by scintillation counting method
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : Bioorg Med Chem
Title : Thiophene bioisosteres of GluN2B selective NMDA receptor antagonists: Synthesis and pharmacological evaluation of [7]annuleno[b]thiophen-6-amines.
Year : 2020
Volume : 28
Issue : 2
First Page : 115245
Last Page : 115245
Authors : Baumeister S, Schepmann D, Wünsch B.
Abstract : Thiophene bioisosteres of potent GluN2B receptor negative allosteric modulators were prepared and evaluated pharmacologically. The five-step synthesis of 4,5,7,8-tetrahydro[7]annuleno[b]thiophen-6-one (10) was considerably improved by carboxylation of thiophene-3-carboxylic acid (8) in the first reaction step. Reductive amination and alkylation led to three homologous series of secondary and tertiary phenylalkylamines 5, 11 and 12. Metalation, reaction with 1-formylpiperidine and subsequent reduction provided hydroxymethyl derivatives 15 and 16, which had been designed as bioisosteres of phenols. 2-Bromo derivatives 18 were obtained by bromination of ketone 10 with NBS and subsequent reductive amination. High GluN2B affinity was achieved with [7]annuleno[b]thiophenes bearing a 3-phenylpropylamino or 4-phenylbutylamino moiety (e.g. 5c: K<sub>i</sub> = 5.9 nM; 11d: K<sub>i</sub> = 9.0 nM). Tertiary ethylamines 12 showed lower GluN2B affinity than tertiary methylamines 11 or secondary amines 5 (e.g. 5c: K<sub>i</sub> = 5.9 nM; 11c: K<sub>i</sub> = 6.0; 12c: K<sub>i</sub> = 51 nM). A Br-atom or a hydroxymethyl moiety in 2-position were less tolerated by the GluN2B receptor. Very similar relationships between the structure and GluN2B affinity and structure and σ affinity, in particular σ<sub>2</sub> affinity, were detected. A slight preference for the ifenprodil binding site of GluN2B receptors over σ<sub>1</sub> and σ<sub>2</sub> receptors was found for methylamines 11c (≈2-fold) and 11d (≈1.5-2-fold) as well as for bromo derivative 18c (≈3-fold).
|
Displacement of [3H]-(+)pentazocine from sigma-1 receptor in guinea pig brain membranes after 120 mins by scintillation counting method
|
Cavia porcellus
|
125.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Synthesis, Cytotoxicity Evaluation, and Computational Insights of Novel 1,4-Diazepane-Based Sigma Ligands.
Year : 2020
Volume : 11
Issue : 5
First Page : 651
Last Page : 656
Authors : Zampieri D, Fortuna S, Calabretti A, Romano M, Menegazzi R, Schepmann D, Wünsch B, Mamolo MG.
Abstract : Among several potential applications, sigma receptor ligands can be used as antipsychotics, antiamnesics, and against other neurodegenerative disorders as well as neuroprotective agents. We present herein a new series of diazepane-containing derivatives as σR ligands obtained by a conformational expansion approach of our previously synthesized piperidine-based compounds. The best results were reached by benzofurane <b>2c</b>, <b>3c</b> and quinoline <b>2d</b>, <b>3d</b>-substituted diazepane derivatives, which showed the highest σR affinity. The cytotoxic activities of synthesized compounds were evaluated against two cancer cell lines, and the results indicated that none of the compounds induced significant toxicity in these cells. We also evaluated the antioxidant activity by radical scavenging capacity of our best compounds on ABTS and H<sub>2</sub>O<sub>2</sub>. The results obtained reveal that our new derivatives possess an excellent antioxidant profile and could be protective for the cells. Overall, the benzofurane derivative <b>2c</b> due to its strong interaction with the active site of the receptor, as confirmed by molecular dynamic simulations, emerged as the optimum compound with high σ1R affinity, low cytotoxicity, and a potent antioxidant activity.
|
Displacement of [3H]-Di-o-tolylguanidine from sigma-2 receptor in rat liver membranes after 120 mins by scintillation counting method
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Synthesis, Cytotoxicity Evaluation, and Computational Insights of Novel 1,4-Diazepane-Based Sigma Ligands.
Year : 2020
Volume : 11
Issue : 5
First Page : 651
Last Page : 656
Authors : Zampieri D, Fortuna S, Calabretti A, Romano M, Menegazzi R, Schepmann D, Wünsch B, Mamolo MG.
Abstract : Among several potential applications, sigma receptor ligands can be used as antipsychotics, antiamnesics, and against other neurodegenerative disorders as well as neuroprotective agents. We present herein a new series of diazepane-containing derivatives as σR ligands obtained by a conformational expansion approach of our previously synthesized piperidine-based compounds. The best results were reached by benzofurane <b>2c</b>, <b>3c</b> and quinoline <b>2d</b>, <b>3d</b>-substituted diazepane derivatives, which showed the highest σR affinity. The cytotoxic activities of synthesized compounds were evaluated against two cancer cell lines, and the results indicated that none of the compounds induced significant toxicity in these cells. We also evaluated the antioxidant activity by radical scavenging capacity of our best compounds on ABTS and H<sub>2</sub>O<sub>2</sub>. The results obtained reveal that our new derivatives possess an excellent antioxidant profile and could be protective for the cells. Overall, the benzofurane derivative <b>2c</b> due to its strong interaction with the active site of the receptor, as confirmed by molecular dynamic simulations, emerged as the optimum compound with high σ1R affinity, low cytotoxicity, and a potent antioxidant activity.
|
Displacement of [3H]ifenprodil from GluN2B (unknown origin) expressed in mouse L(tk-) cell membranes co-expressing GluN1a incubated for 120 mins by scintillation counting method
|
Homo sapiens
|
10.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Synthesis, Cytotoxicity Evaluation, and Computational Insights of Novel 1,4-Diazepane-Based Sigma Ligands.
Year : 2020
Volume : 11
Issue : 5
First Page : 651
Last Page : 656
Authors : Zampieri D, Fortuna S, Calabretti A, Romano M, Menegazzi R, Schepmann D, Wünsch B, Mamolo MG.
Abstract : Among several potential applications, sigma receptor ligands can be used as antipsychotics, antiamnesics, and against other neurodegenerative disorders as well as neuroprotective agents. We present herein a new series of diazepane-containing derivatives as σR ligands obtained by a conformational expansion approach of our previously synthesized piperidine-based compounds. The best results were reached by benzofurane <b>2c</b>, <b>3c</b> and quinoline <b>2d</b>, <b>3d</b>-substituted diazepane derivatives, which showed the highest σR affinity. The cytotoxic activities of synthesized compounds were evaluated against two cancer cell lines, and the results indicated that none of the compounds induced significant toxicity in these cells. We also evaluated the antioxidant activity by radical scavenging capacity of our best compounds on ABTS and H<sub>2</sub>O<sub>2</sub>. The results obtained reveal that our new derivatives possess an excellent antioxidant profile and could be protective for the cells. Overall, the benzofurane derivative <b>2c</b> due to its strong interaction with the active site of the receptor, as confirmed by molecular dynamic simulations, emerged as the optimum compound with high σ1R affinity, low cytotoxicity, and a potent antioxidant activity.
|
Displacement of [3H]ifenprodil from human GluN2B expressed in mouse L(tk-) cell membranes co-expressing GluN1a incubated for 2 hrs by scintillation counting method
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Negative allosteric modulators of the GluN2B NMDA receptor with phenylethylamine structure embedded in ring-expanded and ring-contracted scaffolds.
Year : 2020
Volume : 190
First Page : 112138
Last Page : 112138
Authors : Temme L,Bechthold E,Schreiber JA,Gawaskar S,Schepmann D,Robaa D,Sippl W,Seebohm G,Wünsch B
Abstract : A set of GluN2B NMDA receptor antagonists with conformationally restricted phenylethylamine substructure was prepared and pharmacologically evaluated. The phenylethylamine substructure was embedded in ring expanded 3-benzazocines 4 as well as ring-contracted tetralinamines 6 and indanamines 7. The ligands 4, 6 and 7 were synthesized by reductive alkylation of secondary amine 11, reductive amination of ketones 12 and 16 and nucleophilic substitution of nosylates 14 and 17. The moderate GluN2B affinity of 3-benzazocine 4d (K = 32 nM) translated into moderate cytoprotective activity (IC = 890 nM) and moderate ion channel inhibition (60% at 10 μM) in two-electrode voltage clamp experiments with GluN1a/GluN2B expressing oocytes. Although some of the tetralinamines 6 and indanamines 7 showed very high GluN2B affinity (e.g. K (7f) = 3.2 nM), they could not inhibit glutamate/glycine inducted cytotoxicity. The low cytoprotective activity of 3-benzazocines 4, tetralinamines 6 and indanamines 7 was attributed to the missing OH moiety at the benzene ring and/or in benzylic position. Docking studies showed that the novel GluN2B ligands adopt similar binding poses as Ro 25-6981 with the central H-bond interaction between the protonated amino moiety of the ligands and the carbamoyl moiety of Gln110. However, due to the lack of a second H-bond forming group, the ligands can adopt two binding poses within the ifenprodil binding pocket.
|
Displacement of [3H]-(+)-pentazocine from Sigma1 receptor in guinea pig cortex membranes incubated for 120 mins by scintillation counting method
|
Cavia porcellus
|
125.0
nM
|
|
Journal : Eur J Med Chem
Title : Negative allosteric modulators of the GluN2B NMDA receptor with phenylethylamine structure embedded in ring-expanded and ring-contracted scaffolds.
Year : 2020
Volume : 190
First Page : 112138
Last Page : 112138
Authors : Temme L,Bechthold E,Schreiber JA,Gawaskar S,Schepmann D,Robaa D,Sippl W,Seebohm G,Wünsch B
Abstract : A set of GluN2B NMDA receptor antagonists with conformationally restricted phenylethylamine substructure was prepared and pharmacologically evaluated. The phenylethylamine substructure was embedded in ring expanded 3-benzazocines 4 as well as ring-contracted tetralinamines 6 and indanamines 7. The ligands 4, 6 and 7 were synthesized by reductive alkylation of secondary amine 11, reductive amination of ketones 12 and 16 and nucleophilic substitution of nosylates 14 and 17. The moderate GluN2B affinity of 3-benzazocine 4d (K = 32 nM) translated into moderate cytoprotective activity (IC = 890 nM) and moderate ion channel inhibition (60% at 10 μM) in two-electrode voltage clamp experiments with GluN1a/GluN2B expressing oocytes. Although some of the tetralinamines 6 and indanamines 7 showed very high GluN2B affinity (e.g. K (7f) = 3.2 nM), they could not inhibit glutamate/glycine inducted cytotoxicity. The low cytoprotective activity of 3-benzazocines 4, tetralinamines 6 and indanamines 7 was attributed to the missing OH moiety at the benzene ring and/or in benzylic position. Docking studies showed that the novel GluN2B ligands adopt similar binding poses as Ro 25-6981 with the central H-bond interaction between the protonated amino moiety of the ligands and the carbamoyl moiety of Gln110. However, due to the lack of a second H-bond forming group, the ligands can adopt two binding poses within the ifenprodil binding pocket.
|
Displacement of [3H]DTG from sigma 2 receptor in rat liver membranes incubated for 120 mins by scintillation counting method
|
Rattus norvegicus
|
98.0
nM
|
|
Journal : Eur J Med Chem
Title : Negative allosteric modulators of the GluN2B NMDA receptor with phenylethylamine structure embedded in ring-expanded and ring-contracted scaffolds.
Year : 2020
Volume : 190
First Page : 112138
Last Page : 112138
Authors : Temme L,Bechthold E,Schreiber JA,Gawaskar S,Schepmann D,Robaa D,Sippl W,Seebohm G,Wünsch B
Abstract : A set of GluN2B NMDA receptor antagonists with conformationally restricted phenylethylamine substructure was prepared and pharmacologically evaluated. The phenylethylamine substructure was embedded in ring expanded 3-benzazocines 4 as well as ring-contracted tetralinamines 6 and indanamines 7. The ligands 4, 6 and 7 were synthesized by reductive alkylation of secondary amine 11, reductive amination of ketones 12 and 16 and nucleophilic substitution of nosylates 14 and 17. The moderate GluN2B affinity of 3-benzazocine 4d (K = 32 nM) translated into moderate cytoprotective activity (IC = 890 nM) and moderate ion channel inhibition (60% at 10 μM) in two-electrode voltage clamp experiments with GluN1a/GluN2B expressing oocytes. Although some of the tetralinamines 6 and indanamines 7 showed very high GluN2B affinity (e.g. K (7f) = 3.2 nM), they could not inhibit glutamate/glycine inducted cytotoxicity. The low cytoprotective activity of 3-benzazocines 4, tetralinamines 6 and indanamines 7 was attributed to the missing OH moiety at the benzene ring and/or in benzylic position. Docking studies showed that the novel GluN2B ligands adopt similar binding poses as Ro 25-6981 with the central H-bond interaction between the protonated amino moiety of the ligands and the carbamoyl moiety of Gln110. However, due to the lack of a second H-bond forming group, the ligands can adopt two binding poses within the ifenprodil binding pocket.
|
Cytoprotective activity against glutamate/glycine-induced cell death in mouse L-M(TK-) cells assessed as increase in cell viability incubated for 30 mins followed by glutamate/glycine stimulation and measured after 6 hrs by LDH assay
|
Mus musculus
|
590.0
nM
|
|
Journal : Eur J Med Chem
Title : Negative allosteric modulators of the GluN2B NMDA receptor with phenylethylamine structure embedded in ring-expanded and ring-contracted scaffolds.
Year : 2020
Volume : 190
First Page : 112138
Last Page : 112138
Authors : Temme L,Bechthold E,Schreiber JA,Gawaskar S,Schepmann D,Robaa D,Sippl W,Seebohm G,Wünsch B
Abstract : A set of GluN2B NMDA receptor antagonists with conformationally restricted phenylethylamine substructure was prepared and pharmacologically evaluated. The phenylethylamine substructure was embedded in ring expanded 3-benzazocines 4 as well as ring-contracted tetralinamines 6 and indanamines 7. The ligands 4, 6 and 7 were synthesized by reductive alkylation of secondary amine 11, reductive amination of ketones 12 and 16 and nucleophilic substitution of nosylates 14 and 17. The moderate GluN2B affinity of 3-benzazocine 4d (K = 32 nM) translated into moderate cytoprotective activity (IC = 890 nM) and moderate ion channel inhibition (60% at 10 μM) in two-electrode voltage clamp experiments with GluN1a/GluN2B expressing oocytes. Although some of the tetralinamines 6 and indanamines 7 showed very high GluN2B affinity (e.g. K (7f) = 3.2 nM), they could not inhibit glutamate/glycine inducted cytotoxicity. The low cytoprotective activity of 3-benzazocines 4, tetralinamines 6 and indanamines 7 was attributed to the missing OH moiety at the benzene ring and/or in benzylic position. Docking studies showed that the novel GluN2B ligands adopt similar binding poses as Ro 25-6981 with the central H-bond interaction between the protonated amino moiety of the ligands and the carbamoyl moiety of Gln110. However, due to the lack of a second H-bond forming group, the ligands can adopt two binding poses within the ifenprodil binding pocket.
|
Negative allosteric inhibition of GluN2B (unknown origin) expressed in Oocytes co-expressing GluN1a at 10 uM at -70 mV holding potential by two electrode voltage-clamp assay relative to control
|
Homo sapiens
|
95.0
%
|
|
Journal : Eur J Med Chem
Title : Negative allosteric modulators of the GluN2B NMDA receptor with phenylethylamine structure embedded in ring-expanded and ring-contracted scaffolds.
Year : 2020
Volume : 190
First Page : 112138
Last Page : 112138
Authors : Temme L,Bechthold E,Schreiber JA,Gawaskar S,Schepmann D,Robaa D,Sippl W,Seebohm G,Wünsch B
Abstract : A set of GluN2B NMDA receptor antagonists with conformationally restricted phenylethylamine substructure was prepared and pharmacologically evaluated. The phenylethylamine substructure was embedded in ring expanded 3-benzazocines 4 as well as ring-contracted tetralinamines 6 and indanamines 7. The ligands 4, 6 and 7 were synthesized by reductive alkylation of secondary amine 11, reductive amination of ketones 12 and 16 and nucleophilic substitution of nosylates 14 and 17. The moderate GluN2B affinity of 3-benzazocine 4d (K = 32 nM) translated into moderate cytoprotective activity (IC = 890 nM) and moderate ion channel inhibition (60% at 10 μM) in two-electrode voltage clamp experiments with GluN1a/GluN2B expressing oocytes. Although some of the tetralinamines 6 and indanamines 7 showed very high GluN2B affinity (e.g. K (7f) = 3.2 nM), they could not inhibit glutamate/glycine inducted cytotoxicity. The low cytoprotective activity of 3-benzazocines 4, tetralinamines 6 and indanamines 7 was attributed to the missing OH moiety at the benzene ring and/or in benzylic position. Docking studies showed that the novel GluN2B ligands adopt similar binding poses as Ro 25-6981 with the central H-bond interaction between the protonated amino moiety of the ligands and the carbamoyl moiety of Gln110. However, due to the lack of a second H-bond forming group, the ligands can adopt two binding poses within the ifenprodil binding pocket.
