The Experts below are selected from a list of 1416 Experts worldwide ranked by ideXlab platform
Charles W Emala - One of the best experts on this subject based on the ideXlab platform.
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targeting the restricted α subunit repertoire of airway smooth muscle GABAA Receptors augments airway smooth muscle relaxation
American Journal of Physiology-lung Cellular and Molecular Physiology, 2012Co-Authors: George Gallos, Sucie Chang, William T Gerthoffer, Dingbang Xu, James M Cook, Yi Zhang, Charles W EmalaAbstract:The prevalence of asthma has taken on pandemic proportions. Since this disease predisposes patients to severe acute airway constriction, novel mechanisms capable of promoting airway smooth muscle relaxation would be clinically valuable. We have recently demonstrated that activation of endogenous airway smooth muscle GABAA Receptors potentiates β-adrenoceptor-mediated relaxation, and molecular analysis of airway smooth muscle reveals that the α-subunit component of these GABAA Receptors is limited to the α4- and α5-subunits. We questioned whether ligands with selective affinity for these GABAA Receptors could promote relaxation of airway smooth muscle. RT-PCR analysis of GABAA Receptor subunits was performed on RNA isolated by laser capture microdissection from human and guinea pig airway smooth muscle. Membrane potential and chloride-mediated current were measured in response to GABAA subunit-selective Agonists in cultured human airway smooth muscle cells. Functional relaxation of precontracted guinea pig tracheal rings was assessed in the absence and presence of the α4-subunit-selective GABAA Receptor Agonists: gaboxadol, taurine, and a novel 8-methoxy imidazobenzodiazepine (CM-D-45). Only messenger RNA encoding the α4- and α5-GABAA Receptor subunits was identified in RNA isolated by laser capture dissection from guinea pig and human airway smooth muscle tissues. Activation of airway smooth muscle GABAA Receptors with Agonists selective for these subunits resulted in appropriate membrane potential changes and chloride currents and promoted relaxation of airway smooth muscle. In conclusion, selective subunit targeting of endogenous airway smooth muscle-specific GABAA Receptors may represent a novel therapeutic option for patients in severe bronchospasm.
Bente Frolund - One of the best experts on this subject based on the ideXlab platform.
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synthesis and pharmacological evaluation of 6 aminonicotinic acid analogues as novel GABAA Receptor Agonists
European Journal of Medicinal Chemistry, 2014Co-Authors: Jette G Petersen, Troels E Sorensen, Maria Damgaard, Birgitte Nielsen, Anders A Jensen, Thomas Balle, Rikke Bergmann, Bente FrolundAbstract:Abstract A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABAA Receptors. 6-Aminonicotinic acid (3) as well as 2- and 4-alkylated analogues (9–11, 14–16) display low to mid-micromolar GABAAR binding affinities to native GABAA Receptors (Ki 1.1–24 μM). The tetrahydropyridine analogue of 3 (22) shows low-nanomolar affinity (Ki 0.044 μM) and equipotency as an agonist to GABA itself as well as the standard GABAA agonist isoguvacine. Cavities surrounding the core of the GABA binding pocket were predicted by molecular interaction field calculations and docking studies in a α1β2γ2 GABAA Receptor homology model, and were confirmed by affinities of substituted analogues of 3. The tight steric requirements observed for the remarkably few GABAAR Agonists reported to date is challenged by our findings. New openings for agonist design are proposed which potentially could facilitate the exploration of different pharmacological profiles within the GABAAR area.
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Specific GABA(A) Agonists and partial Agonists.
Chemical Record, 2002Co-Authors: Povl Krogsgaard-larsen, Bente Frolund, Tommy LiljeforsAbstract:The GABAA Receptor system is implicated in a number of neurological and psychiatric diseases, making GABAA Receptor ligands interesting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on the hetero-pentameric GABAA Receptor complex, reflecting the very strict structural requirements for GABAA Receptor recognition and activation. Within the series of compounds showing agonist activity at the GABAA Receptor site that have been developed, most of the ligands are structurally derived from the GABAA Agonists muscimol, THIP, or isoguvacine, which we developed in the initial stages of the project. Using recombinant GABAA Receptors, functional selectivity was demonstrated for a number of compounds, including THIP, showing highly subunit-dependent potency and maximal response. In light of the interest in partial GABAA Receptor Agonists as potential therapeutics, structure–activity studies of a number of analogs of 4-PIOL, a low-efficacy partial GABAA agonist derived from THIP, have been performed. In this connection, a series of GABAA ligands has been developed that exhibit pharmacological profiles from moderately potent low-efficacy partial GABAA agonist activity to potent and selective antagonist effects. Very little information is available on direct-acting GABAA Receptor Agonists in clinical studies. However, the results of clinical studies on the effect of the partial GABAA agonist THIP on human sleep patterns show that the functional consequences of a direct-acting agonist are different from those seen after the administration of GABAA Receptor modulators, such as benzodiazepines and barbiturates. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc., Chem Rec 2: 419–430; 2002: Published online in Wiley Interscience (www.interscience.wiley.com) DOI 10.1002/tcr.10040
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GABAA Receptor Agonists partial Agonists and antAgonists
1997Co-Authors: Povl Krogsgaardlarsen, Bente Frolund, Bjarke EbertAbstract:The neutral amino acid, γ-aminobutyric acid (GABA), is an inhibitory transmitter in the central nervous system (CNS). Furthermore, GABA is involved as a neurotransmitter and/or a paracrine effector in the regulation of a variety of physiological mechanisms in the periphery. Some of these latter functions may be under central GABA control; others are managed by local GABA neurons. A large percentage, perhaps the majority, of central neurons are under GABA control. The complex mechanisms underlying the GABA-mediated neurotransmission have been extensively studied, using a broad spectrum of electrophysiological, neurochemical, pharmacological, and in recent years, molecular biological techniques (Krnjevic, 1974; Curtis and Johnston, 1974; Olsen and Venter, 1986; Redburn and Schousboe, 1987; Bowery and Nistico, 1989; Bowery et al., 1990; Biggio and Costa, 1990; Schousboe et al., 1992a).
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partial GABAA Receptor Agonists synthesis and in vitro pharmacology of a series of nonannulated analogs of 4 5 6 7 tetrahydroisoxazolo 5 4 c pyridin 3 ol
Journal of Medicinal Chemistry, 1995Co-Authors: Bente Frolund, Povl Krogsgaardlarsen, Uffe Kristiansen, Lotte Brehm, Annette B Hansen, Erik FalchAbstract:5-(4-Piperidyl)isoxazol-3-ol (4-PIOL, 10), a structural analog of 4-aminobutanoic acid (GABA, 1) and the GABAA agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 5), is a low-efficacy partial GABAA agonist. A number of compounds bioisosterically derived from 10, including 5-(4-piperidyl)isothiazol-3-ol (11), 3-(4-piperidyl)isoxazol-5-ol (12), 5-(1,2,3,6-tetrahydropyrid-4-yl)isoxazol-3-ol (13), and 5-(1,2,3,6-tetrahydropyrid-4-yl)isothiazol-3-ol (14), were synthesized and tested as GABAA Receptor ligands. Whereas none of these compounds significantly affected GABAB Receptor binding or GABA uptake, they showed affinities for GABAA Receptor sites in the low-micromolar range. Using cultured cerebral cortical neurons and whole-cell patch-clamp techniques, the efficacies of these compounds relative to that of the full GABAA agonist, isoguvacine (8) (20 microM), were determined. The relative efficacy of 11, which has a higher Receptor affinity (IC50 = 1.3 +/- 0.3 microM) than 10 (IC50 = 9.3 +/- 2.6 microM), was comparable with that of 10 (30-35%). The tetrahydropyridine analog of 10, compound 13, showed a markedly lower Receptor affinity (IC50 = 32 +/- 10 microM) and apparently a lower relative efficacy than 10. The corresponding unsaturated analog of 11, compound 14, showed a slightly weaker Receptor affinity (IC50 = 4.0 +/- 2.0 microM) but a significantly higher relative efficacy (50-55%) than 11. The 5-isoxazolol isomer of 10, compound 12, showed a reduced Receptor affinity (IC50 = 26 +/- 7 microM) and a very low relative efficacy. Substitution of propanoic or propenoic acid moieties for the acidic heterocyclic units of these compounds gave the monocyclic amino acids 15-18, which have very little or no affinity for GABAA Receptor sites.
Bjarke Ebert - One of the best experts on this subject based on the ideXlab platform.
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lack of generalisation between the GABAA Receptor agonist gaboxadol and allosteric modulators of the benzodiazepine binding site in the rat drug discrimination procedure
Psychopharmacology, 2007Co-Authors: Signe Michelsen, Connie Sanchez, Bjarke EbertAbstract:The binding sites for γ-aminobutyric acid (GABA) and GABAA Receptor Agonists are located differently from the binding sites for benzodiazepine Receptor Agonists. Furthermore, the major pharmacological effects of benzodiazepine Receptor Agonists and the GABAA Receptor agonist gaboxadol (4,5,6,7-tetrahydrroisoxazolo(5,4-c)pyridin-3-ol, THIP) are mediated by different GABAA Receptor subunit compositions; that is, gaboxadol may interact primarily with extra-synaptically located α4β2/3δ-containing Receptors and benzodiazepines with the synaptically located α1β2/3γ2-containing Receptors. The aim of the present study was to address if this different Receptor subtype selectivity was reflected in vivo. A two-lever liquid reinforced operant discrimination procedure was conducted. Three groups of rats were trained to discriminate gaboxadol, diazepam and zolpidem 5.5, 1.5 and 0.7 mg/kg i.p., respectively, from vehicle. Substitution tests showed that gaboxadol-trained animals failed to recognize diazepam (0.75–1.5 mg/kg), zolpidem (0.4–0.7 mg/kg), zopiclone (2.5 mg/kg), zaleplon (1.0–1.5 mg/kg) or indiplon (0.31 mg/kg). In contrast, all benzodiazepine Receptor Agonists, but not gaboxadol (4.5–5.5 mg/kg), generalised to the discriminative stimulus in diazepam- and zolpidem-trained animals. In agreement with these data, the competitive benzodiazepine Receptor antagonist flumazenil (10 mg/kg s.c.) antagonised the discriminative stimulus of zolpidem but not of gaboxadol. Interaction tests showed no synergistic interaction of concomitant administration of gaboxadol and zolpidem or diazepam. Previous studies have shown that gaboxadol and benzodiazepines interact with different Receptor populations, and the present study confirms that in vivo functional consequences of this Receptor selectivity exist in the form of differential behavioural responses in rats.
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effects of GABAA Receptor partial Agonists in primary cultures of cerebellar granule neurons and cerebral cortical neurons reflect different Receptor subunit compositions
British Journal of Pharmacology, 2001Co-Authors: Suzanne L Hansen, Bjarke Ebert, Bjarne Fjalland, Uffe KristiansenAbstract:Based on an unexpected high maximum response to piperidine-4-sulphonic acid (P4S) at human α1α6β2γ2 GABAA Receptors expressed in Xenopus oocytes attempts to correlate this finding with the pharmacological profile of P4S and other GABAA Receptor ligands in neuronal cultures from rat cerebellar granule cells and rat cerebral cortex were carried out. GABA and isoguvacine acted as full and piperidine-4-sulphonic acid (P4S) as partial Agonists, respectively, at α1β2γ2, α6β2γ2 and α1α6β2γ2 GABA Receptors expressed in Xenopus oocytes with differences in potency. Whole-cell patch-clamp recordings were used to investigate the pharmacological profile of the partial GABAA Receptor Agonists 4,5,6,7-tetrahydroisoxazolo-(5,4-c)pyridin-3-ol (THIP), P4S, 5-(4-piperidyl)isoxazol-3-ol (4-PIOL), and 3-(4-piperidyl)isoxazol-5-ol (iso-4-PIOL), and the competitive GABAA Receptor antAgonists Bicuculline Methbromide (BMB) and 2-(3-carboxypropyl)-3-amino-6-methoxyphenyl-pyridazinium bromide (SR95531) on cerebral cortical and cerebellar granule neurons. In agreement with findings in oocytes, GABA, isoguvacine and P4S showed similar pharmacological profiles in cultured cortical and cerebellar neurones, which are known to express mainly α1, α2, α3, and α5 containing Receptors and α1, α6 and α1α6 containing Receptors, respectively. 4-PIOL and iso-4-PIOL, which at GABAA Receptors expressed in oocytes were weak antAgonists, showed cell type dependent potency as inhibitors of GABA mediated responses. Thus, 4-PIOL was slightly more potent at cortical neurones than at granule neurones and iso-4-PIOL was more potent in inhibiting isoguvacine-evoked currents at cortical than at granule neurons. Furthermore the maximum response to 4-PIOL corresponded to that of a partial agonist, whereas that of iso-4-PIOL gave a maximum response close to zero. It is concluded that the pharmacological profile of partial Agonists is highly dependent on the Receptor composition, and that small structural changes of a ligand can alter the selectivity towards different subunit compositions. Moreover, this study shows that pharmacological actions determined in oocytes are generally in agreement with data obtained from cultured neurons. British Journal of Pharmacology (2001) 133, 539–549; doi:10.1038/sj.bjp.0704121
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GABAA Receptor Agonists partial Agonists and antAgonists
1997Co-Authors: Povl Krogsgaardlarsen, Bente Frolund, Bjarke EbertAbstract:The neutral amino acid, γ-aminobutyric acid (GABA), is an inhibitory transmitter in the central nervous system (CNS). Furthermore, GABA is involved as a neurotransmitter and/or a paracrine effector in the regulation of a variety of physiological mechanisms in the periphery. Some of these latter functions may be under central GABA control; others are managed by local GABA neurons. A large percentage, perhaps the majority, of central neurons are under GABA control. The complex mechanisms underlying the GABA-mediated neurotransmission have been extensively studied, using a broad spectrum of electrophysiological, neurochemical, pharmacological, and in recent years, molecular biological techniques (Krnjevic, 1974; Curtis and Johnston, 1974; Olsen and Venter, 1986; Redburn and Schousboe, 1987; Bowery and Nistico, 1989; Bowery et al., 1990; Biggio and Costa, 1990; Schousboe et al., 1992a).
George Gallos - One of the best experts on this subject based on the ideXlab platform.
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targeting the restricted α subunit repertoire of airway smooth muscle GABAA Receptors augments airway smooth muscle relaxation
American Journal of Physiology-lung Cellular and Molecular Physiology, 2012Co-Authors: George Gallos, Sucie Chang, William T Gerthoffer, Dingbang Xu, James M Cook, Yi Zhang, Charles W EmalaAbstract:The prevalence of asthma has taken on pandemic proportions. Since this disease predisposes patients to severe acute airway constriction, novel mechanisms capable of promoting airway smooth muscle relaxation would be clinically valuable. We have recently demonstrated that activation of endogenous airway smooth muscle GABAA Receptors potentiates β-adrenoceptor-mediated relaxation, and molecular analysis of airway smooth muscle reveals that the α-subunit component of these GABAA Receptors is limited to the α4- and α5-subunits. We questioned whether ligands with selective affinity for these GABAA Receptors could promote relaxation of airway smooth muscle. RT-PCR analysis of GABAA Receptor subunits was performed on RNA isolated by laser capture microdissection from human and guinea pig airway smooth muscle. Membrane potential and chloride-mediated current were measured in response to GABAA subunit-selective Agonists in cultured human airway smooth muscle cells. Functional relaxation of precontracted guinea pig tracheal rings was assessed in the absence and presence of the α4-subunit-selective GABAA Receptor Agonists: gaboxadol, taurine, and a novel 8-methoxy imidazobenzodiazepine (CM-D-45). Only messenger RNA encoding the α4- and α5-GABAA Receptor subunits was identified in RNA isolated by laser capture dissection from guinea pig and human airway smooth muscle tissues. Activation of airway smooth muscle GABAA Receptors with Agonists selective for these subunits resulted in appropriate membrane potential changes and chloride currents and promoted relaxation of airway smooth muscle. In conclusion, selective subunit targeting of endogenous airway smooth muscle-specific GABAA Receptors may represent a novel therapeutic option for patients in severe bronchospasm.
David A. Taylor - One of the best experts on this subject based on the ideXlab platform.
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Alterations in Neuronal γ-Aminobutyric AcidAReceptor Responsiveness in Genetic Models of Seizure Susceptibility with Different Expression Patterns
The Journal of pharmacology and experimental therapeutics, 2000Co-Authors: Lance R. Molnar, William W. Fleming, David A. TaylorAbstract:The genetically epilepsy-prone rat (GEPR) is a unique animal model of seizure predisposition with substrains (i.e., GEPR-NE, GEPR-3, and GEPR-9) that exhibit different seizure patterns in response to the same stimulus. Among many deficits identified in these animals, reduced responses to GABAA Receptor Agonists have been described in several brain regions of the GEPR-9. However, few studies have quantitatively analyzed this difference in responsiveness or have examined and compared the responsiveness of GEPR-3 neurons with the other strains. Using intracellular recording, we determined and compared the responsiveness of Purkinje neurons from GEPR-3 animals with those of control (both Sprague-Dawley and GEPR-NE) and GEPR-9 rats at different developmental ages. In GEPR-9 animals, the EC50 value for GABA and muscimol was shifted 3-fold to the right, with no reduction in maximum. In contrast, GEPR-3 animals showed a significant reduction in the maximum hyperpolarizing response to only GABA and muscimol with no change in the EC50 values. Responsiveness to glutamate, aspartate, norepinephrine, and diazepam was unchanged in both strains, indicating that the change in responsiveness was highly selective for GABAA Receptor Agonists. Changes in responsiveness in animals