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Klaus T. Wanner - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological evaluation of novel N-substituted Nipecotic Acid derivatives with tricyclic cage structures in the lipophilic domain as GABA uptake inhibitors
Medicinal Chemistry Research, 2020Co-Authors: Heinrich-karl A. Rudy, Georg Höfner, Klaus T. WannerAbstract:A new class of GABA reuptake inhibitors with sterically demanding, highly rigid tricyclic cage structures as the lipophilic domain was synthesized and investigated in regard to their biological activity at the murine GABA transporters (mGAT1–mGAT4). The construction of these compounds, consisting of Nipecotic Acid, a symmetric tricyclic amine, and a plain hydrocarbon linker connecting the two subunits via their amino nitrogens, was accomplished via reductive amination of a Nipecotic Acid derivative with an N -alkyl substituent displaying a terminal aldehyde function with tricyclic secondary amines. The target compounds varied with regard to spacer length, the bridge size of one of the bridges, and the substituents of the tricyclic skeleton to study the impact of these changes on their potency. Among the tested compounds Nipecotic Acid ethyl ester derivates with phenyl residues attached to the cage subunit showed reasonable inhibitory potency and subtype selectivity in favor of mGAT3 and mGAT4, respectively.
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synthesis and biological evaluation of Nipecotic Acid and guvacine derived 1 3 disubstituted allenes as inhibitors of murine gaba transporter mgat1
ChemMedChem, 2019Co-Authors: Maren Schaarschmidt, Georg Höfner, Klaus T. WannerAbstract:A new class of Nipecotic Acid and guvacine derivatives has been synthesized and characterized for their inhibitory potency at mGAT1-4 and binding affinity for mGAT1. Compounds of the described class are defined by a four-carbon-atom allenyl spacer connecting the nitrogen atom of the Nipecotic Acid or guvacine head with an aromatic residue. Among the compounds investigated, the mixture of Nipecotic Acid derivatives rac-{(Ra )-1-[4-([1,1':2',1''-terphenyl]-2-yl)buta-2,3-dien-1-yl](3R)-piperidine-3-carboxylic Acid} and rac-{(Sa )-1-[4-([1,1':2',1''-terphenyl]-2-yl)buta-2,3-dien-1-yl](3R)-piperidine-3-carboxylic Acid} (21 p), possessing an o-terphenyl residue, was identified as highly selective and the most potent mGAT1 inhibitor in this study. For the (R)-Nipecotic Acid derived form of 21 p, the inhibitory potency in [3 H]GABA uptake assays was determined as pIC50 =6.78±0.08, and the binding affinity in MS Binding Assays as pKi =7.10±0.12. The synthesis of the designed compounds was carried out by a two-step procedure, generating the allene moiety via allenylation of terminal alkynes which allows broad variation of the terminal phenyl and biphenyl subunit.
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ms based screening of 5 substituted Nipecotic Acid derived hydrazone libraries as ligands of the gaba transporter 1
ChemMedChem, 2019Co-Authors: Tobias J Hauke, Georg Höfner, Klaus T. WannerAbstract:A screening of compound libraries based on Nipecotic Acid derivatives with lipophilic residues attached to the scarcely explored 5-position of the core structure was used for the search of new inhibitors of the γ-aminobutyric Acid (GABA) transporter 1 (mGAT1). The generated compound libraries, which were based on hydrazone chemistry commonly used in dynamic combinatorial chemistry but rendered pseudostatic, were screened for their binding affinities toward mGAT1 by means of MS Binding Assays. With Nipecotic Acid derived hydrazone rac-16 h [rac-(3R,5S)-{5-[(E)-2-{[5-(2-phenylethynyl)thiophen-2-yl]methylidene}hydrazin-1-yl]piperidine-3-carboxylic Acid}-sodium chloride (1/2)], one hit was found and evaluated displaying sub-micromolar potency (pKi =6.62±0.04) and a noncompetitive interaction mode at mGAT1. By bearing a 5-(2-phenylethynyl)thiophen-2-yl residue attached to the 5-position of Nipecotic Acid via a three-atom spacer, compound rac-16 h contains a structural moiety so far unprecedented for these kinds of bioactive molecules, and complements novel 5-substituted Nipecotic Acid derived ligands of mGAT1 revealed in a recently published screening campaign. This new class of ligands, with an inhibition mode distinct from that of benchmark mGAT1 inhibitors, could serve as research tools for investigations of mGAT1-mediated GABA transport.
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synthesis and biological evaluation of novel n substituted Nipecotic Acid derivatives with a cis alkene spacer as gaba uptake inhibitors
Bioorganic & Medicinal Chemistry, 2018Co-Authors: Krisztian Toth, Georg Höfner, Klaus T. WannerAbstract:Our study presents the synthesis and structure-activity relationship (SAR) of novel N-substituted Nipecotic Acid derivatives closely related to DDPM-1457 [(S)-2a], a chemically stable analog of (S)-SNAP-5114 (1), in the pursuit of finding new and potent mGAT4 selective inhibitors. Iminium ion chemistry served as key step for the preparation of the desired, new N-substituted Nipecotic Acid derivatives containing a variety of different heterocycles attached to the Nipecotic Acid moiety via a trans-alkene spacer. The target compounds were characterized with regard to their potency at and subtype selectivity for the GABA transporters mGAT1-mGAT4.
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development of new photoswitchable azobenzene based γ aminobutyric Acid gaba uptake inhibitors with distinctly enhanced potency upon photoactivation
Journal of Medicinal Chemistry, 2018Co-Authors: Toni A. Lutz, Georg Höfner, Jorg Pabel, Thomas Wein, Matthias Eder, Julien Dine, Klaus T. WannerAbstract:A series of Nipecotic Acid derivatives with new azo benzene based photoswitchable N-substituents was synthesized and characterized in their (E)- and (Z)-form for their functional inhibitory activity at γ-aminobutyric Acid transporters subtype 1 (GAT1), the most common γ-aminobutyric Acid (GABA) transporter subtype in the central nervous system (CNS). This led to the identification of the first photoswitchable ligands exhibiting a moderate uptake inhibition of GABA in their (E)- but distinctive higher inhibitory potency in their (Z)-form resulting from photoirradiation. For the most efficient photoactivatable Nipecotic Acid derivative displaying an N-but-3-yn-1-yl linker with a terminal diphenyldiazene unit, an inhibitory potency of 4.65 ± 0.05 (pIC50) was found for its (E)-form. which increased by almost two log units up to 6.38 ± 0.04 when irradiated. The effect of this photoswitchable mGAT1 inhibitor has also been evaluated and confirmed in patch-clamp recordings in acute hippocampal slices from mice.
Georg Höfner - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological evaluation of novel N-substituted Nipecotic Acid derivatives with tricyclic cage structures in the lipophilic domain as GABA uptake inhibitors
Medicinal Chemistry Research, 2020Co-Authors: Heinrich-karl A. Rudy, Georg Höfner, Klaus T. WannerAbstract:A new class of GABA reuptake inhibitors with sterically demanding, highly rigid tricyclic cage structures as the lipophilic domain was synthesized and investigated in regard to their biological activity at the murine GABA transporters (mGAT1–mGAT4). The construction of these compounds, consisting of Nipecotic Acid, a symmetric tricyclic amine, and a plain hydrocarbon linker connecting the two subunits via their amino nitrogens, was accomplished via reductive amination of a Nipecotic Acid derivative with an N -alkyl substituent displaying a terminal aldehyde function with tricyclic secondary amines. The target compounds varied with regard to spacer length, the bridge size of one of the bridges, and the substituents of the tricyclic skeleton to study the impact of these changes on their potency. Among the tested compounds Nipecotic Acid ethyl ester derivates with phenyl residues attached to the cage subunit showed reasonable inhibitory potency and subtype selectivity in favor of mGAT3 and mGAT4, respectively.
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synthesis and biological evaluation of Nipecotic Acid and guvacine derived 1 3 disubstituted allenes as inhibitors of murine gaba transporter mgat1
ChemMedChem, 2019Co-Authors: Maren Schaarschmidt, Georg Höfner, Klaus T. WannerAbstract:A new class of Nipecotic Acid and guvacine derivatives has been synthesized and characterized for their inhibitory potency at mGAT1-4 and binding affinity for mGAT1. Compounds of the described class are defined by a four-carbon-atom allenyl spacer connecting the nitrogen atom of the Nipecotic Acid or guvacine head with an aromatic residue. Among the compounds investigated, the mixture of Nipecotic Acid derivatives rac-{(Ra )-1-[4-([1,1':2',1''-terphenyl]-2-yl)buta-2,3-dien-1-yl](3R)-piperidine-3-carboxylic Acid} and rac-{(Sa )-1-[4-([1,1':2',1''-terphenyl]-2-yl)buta-2,3-dien-1-yl](3R)-piperidine-3-carboxylic Acid} (21 p), possessing an o-terphenyl residue, was identified as highly selective and the most potent mGAT1 inhibitor in this study. For the (R)-Nipecotic Acid derived form of 21 p, the inhibitory potency in [3 H]GABA uptake assays was determined as pIC50 =6.78±0.08, and the binding affinity in MS Binding Assays as pKi =7.10±0.12. The synthesis of the designed compounds was carried out by a two-step procedure, generating the allene moiety via allenylation of terminal alkynes which allows broad variation of the terminal phenyl and biphenyl subunit.
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ms based screening of 5 substituted Nipecotic Acid derived hydrazone libraries as ligands of the gaba transporter 1
ChemMedChem, 2019Co-Authors: Tobias J Hauke, Georg Höfner, Klaus T. WannerAbstract:A screening of compound libraries based on Nipecotic Acid derivatives with lipophilic residues attached to the scarcely explored 5-position of the core structure was used for the search of new inhibitors of the γ-aminobutyric Acid (GABA) transporter 1 (mGAT1). The generated compound libraries, which were based on hydrazone chemistry commonly used in dynamic combinatorial chemistry but rendered pseudostatic, were screened for their binding affinities toward mGAT1 by means of MS Binding Assays. With Nipecotic Acid derived hydrazone rac-16 h [rac-(3R,5S)-{5-[(E)-2-{[5-(2-phenylethynyl)thiophen-2-yl]methylidene}hydrazin-1-yl]piperidine-3-carboxylic Acid}-sodium chloride (1/2)], one hit was found and evaluated displaying sub-micromolar potency (pKi =6.62±0.04) and a noncompetitive interaction mode at mGAT1. By bearing a 5-(2-phenylethynyl)thiophen-2-yl residue attached to the 5-position of Nipecotic Acid via a three-atom spacer, compound rac-16 h contains a structural moiety so far unprecedented for these kinds of bioactive molecules, and complements novel 5-substituted Nipecotic Acid derived ligands of mGAT1 revealed in a recently published screening campaign. This new class of ligands, with an inhibition mode distinct from that of benchmark mGAT1 inhibitors, could serve as research tools for investigations of mGAT1-mediated GABA transport.
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synthesis and biological evaluation of novel n substituted Nipecotic Acid derivatives with a cis alkene spacer as gaba uptake inhibitors
Bioorganic & Medicinal Chemistry, 2018Co-Authors: Krisztian Toth, Georg Höfner, Klaus T. WannerAbstract:Our study presents the synthesis and structure-activity relationship (SAR) of novel N-substituted Nipecotic Acid derivatives closely related to DDPM-1457 [(S)-2a], a chemically stable analog of (S)-SNAP-5114 (1), in the pursuit of finding new and potent mGAT4 selective inhibitors. Iminium ion chemistry served as key step for the preparation of the desired, new N-substituted Nipecotic Acid derivatives containing a variety of different heterocycles attached to the Nipecotic Acid moiety via a trans-alkene spacer. The target compounds were characterized with regard to their potency at and subtype selectivity for the GABA transporters mGAT1-mGAT4.
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development of new photoswitchable azobenzene based γ aminobutyric Acid gaba uptake inhibitors with distinctly enhanced potency upon photoactivation
Journal of Medicinal Chemistry, 2018Co-Authors: Toni A. Lutz, Georg Höfner, Jorg Pabel, Thomas Wein, Matthias Eder, Julien Dine, Klaus T. WannerAbstract:A series of Nipecotic Acid derivatives with new azo benzene based photoswitchable N-substituents was synthesized and characterized in their (E)- and (Z)-form for their functional inhibitory activity at γ-aminobutyric Acid transporters subtype 1 (GAT1), the most common γ-aminobutyric Acid (GABA) transporter subtype in the central nervous system (CNS). This led to the identification of the first photoswitchable ligands exhibiting a moderate uptake inhibition of GABA in their (E)- but distinctive higher inhibitory potency in their (Z)-form resulting from photoirradiation. For the most efficient photoactivatable Nipecotic Acid derivative displaying an N-but-3-yn-1-yl linker with a terminal diphenyldiazene unit, an inhibitory potency of 4.65 ± 0.05 (pIC50) was found for its (E)-form. which increased by almost two log units up to 6.38 ± 0.04 when irradiated. The effect of this photoswitchable mGAT1 inhibitor has also been evaluated and confirmed in patch-clamp recordings in acute hippocampal slices from mice.
Lars J S Knutsen - One of the best experts on this subject based on the ideXlab platform.
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the synthesis of novel gaba uptake inhibitors 1 elucidation of the structure activity studies leading to the choice of r 1 4 4 bis 3 methyl 2 thienyl 3 butenyl 3 piperidinecarboxylic Acid tiagabine as an anticonvulsant drug candidate
Journal of Medicinal Chemistry, 1993Co-Authors: Knud Erik Andersen, Claus Braestrup, Ursula Sonnewald, Peter D Suzdak, F C Gronwald, Anker Steen Jorgensen, E B Nielsen, Per Olaf Huusfeldt, Lars J S KnutsenAbstract:A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of Nipecotic Acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [3H]-GABA uptake in rat synaptosomes was determined for each compound. It was found that the most potent examples are those having a substituent in an "ortho" position in one or both aromatic/heteroaromatic groups. The majority of the compounds described are structurally related to tiagabine, (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidinecarboxylic Acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.
Helen A Baghdoyan - One of the best experts on this subject based on the ideXlab platform.
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γ aminobutyric Acid mediated neurotransmission in the pontine reticular formation modulates hypnosis immobility and breathing during isoflurane anesthesia
Anesthesiology, 2008Co-Authors: Giancarlo Vanini, Ralph Lydic, Chris J Watson, Helen A BaghdoyanAbstract:BACKGROUND: Many general anesthetics are thought to produce a loss of wakefulness, in part, by enhancing gamma-aminobutyric Acid (GABA) neurotransmission. However, GABAergic neurotransmission in the pontine reticular formation promotes wakefulness. This study tested the hypotheses that (1) relative to wakefulness, isoflurane decreases GABA levels in the pontine reticular formation; and (2) pontine reticular formation administration of drugs that increase or decrease GABA levels increases or decreases, respectively, isoflurane induction time. METHODS: To test hypothesis 1, cats (n = 5) received a craniotomy and permanent electrodes for recording the electroencephalogram and electromyogram. Dialysis samples were collected from the pontine reticular formation during isoflurane anesthesia and wakefulness. GABA levels were quantified using high-performance liquid chromatography. For hypothesis 2, rats (n = 10) were implanted with a guide cannula aimed for the pontine reticular formation. Each rat received microinjections of Ringer's (vehicle control), the GABA uptake inhibitor Nipecotic Acid, and the GABA synthesis inhibitor 3-mercaptopropionic Acid. Rats were then anesthetized with isoflurane, and induction time was quantified as loss of righting reflex. Breathing rate was also measured. RESULTS: Relative to wakefulness, GABA levels were significantly decreased by isoflurane. Increased power in the electroencephalogram and decreased activity in the electromyogram caused by isoflurane covaried with pontine reticular formation GABA levels. Nipecotic Acid and 3-mercaptopropionic Acid significantly increased and decreased, respectively, isoflurane induction time. Nipecotic Acid also increased breathing rate. CONCLUSION: Decreasing pontine reticular formation GABA levels comprises one mechanism by which isoflurane causes loss of consciousness, altered cortical excitability, muscular hypotonia, and decreased respiratory rate.
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sleep and gaba levels in the oral part of rat pontine reticular formation are decreased by local and systemic administration of morphine
Neuroscience, 2007Co-Authors: Chris J Watson, Ralph Lydic, Helen A BaghdoyanAbstract:Abstract Morphine, a μ-opioid receptor agonist, is a commonly prescribed treatment for pain. Although highly efficacious, morphine has many unwanted side effects including disruption of sleep and obtundation of wakefulness. One mechanism by which morphine alters sleep and wakefulness may be by modulating GABAergic signaling in brain regions regulating arousal, including the pontine reticular nucleus, oral part (PnO). This study used in vivo microdialysis in unanesthetized Sprague–Dawley rat to test the hypothesis that μ-opioid receptors modulate PnO GABA levels. Validation of the high performance liquid chromatographic technique used to quantify GABA was obtained by dialyzing the PnO ( n =4 rats) with the GABA reuptake inhibitor Nipecotic Acid (500 μM). Nipecotic Acid caused a 185±20% increase in PnO GABA levels, confirming chromatographic detection of GABA and demonstrating the existence of functional GABA transporters in rat PnO. Morphine caused a concentration-dependent decrease in PnO GABA levels ( n =25 rats). Coadministration of morphine (100 μM) with naloxone (1 μM), a μ-opioid receptor antagonist, blocked the morphine-induced decrease in PnO GABA levels ( n =5 rats). These results show for the first time that μ-opioid receptors in rat PnO modulate GABA levels. A second group of rats ( n =6) was used to test the hypothesis that systemically administered morphine also decreases PnO GABA levels. I.v. morphine caused a significant ( P n =8 rats). Morphine significantly ( P P
Toni A. Lutz - One of the best experts on this subject based on the ideXlab platform.
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development of new photoswitchable azobenzene based γ aminobutyric Acid gaba uptake inhibitors with distinctly enhanced potency upon photoactivation
Journal of Medicinal Chemistry, 2018Co-Authors: Toni A. Lutz, Georg Höfner, Jorg Pabel, Thomas Wein, Matthias Eder, Julien Dine, Klaus T. WannerAbstract:A series of Nipecotic Acid derivatives with new azo benzene based photoswitchable N-substituents was synthesized and characterized in their (E)- and (Z)-form for their functional inhibitory activity at γ-aminobutyric Acid transporters subtype 1 (GAT1), the most common γ-aminobutyric Acid (GABA) transporter subtype in the central nervous system (CNS). This led to the identification of the first photoswitchable ligands exhibiting a moderate uptake inhibition of GABA in their (E)- but distinctive higher inhibitory potency in their (Z)-form resulting from photoirradiation. For the most efficient photoactivatable Nipecotic Acid derivative displaying an N-but-3-yn-1-yl linker with a terminal diphenyldiazene unit, an inhibitory potency of 4.65 ± 0.05 (pIC50) was found for its (E)-form. which increased by almost two log units up to 6.38 ± 0.04 when irradiated. The effect of this photoswitchable mGAT1 inhibitor has also been evaluated and confirmed in patch-clamp recordings in acute hippocampal slices from mice.
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Focused Pseudostatic Hydrazone Libraries Screened by Mass Spectrometry Binding Assay: Optimizing Affinities toward γ‑Aminobutyric Acid Transporter 1
2016Co-Authors: Miriam Sindelar, Toni A. Lutz, Marilena Petrera, Klaus T. WannerAbstract:Mass spectrometric (MS) binding assays, a powerful tool to determine affinities of single drug candidates toward chosen targets, were recently demonstrated to be suitable for the screening of compound libraries generated with reactions of dynamic combinatorial chemistry when rendering libraries pseudostatic. Screening of small hydrazone libraries targeting γ-aminobutyric Acid transporter 1 (GAT1), the most abundant γ-aminobutyric Acid (GABA) transporter in the central nervous system, revealed two Nipecotic Acid derived binders with submicromolar affinities. Starting from the biphenyl carrying hit as lead structure, the objective of the present study was to discover novel high affinity GAT1 binders by screening of biphenyl focused pseudostatic hydrazone libraries formed from hydrazine 10 and 36 biphenylcarbaldehydes 11c–al. Hydrazone 12z that carried a 2′,4′-dichlorobiphenyl residue was found to be the most potent binder with low nanomolar affinity (pKi = 8.094 ± 0.098). When stable carba analogues of representative hydrazones were synthesized and evaluated, the best binder 13z was again displaying the 2′,4′-dichlorobiphenyl moiety (pKi = 6.930 ± 0.021)