An Updated Unified Pharmacophore Model of the Benzodiazepine Binding Site on &amp;#947;-Aminobutyric Acida Receptors: Correlation with Comparative Models

Clayton, Terry; Chen, J. L.; Ernst, Margot; Richter, Lars; Cromer, Brett A.; Morton, Craig J.; Ng, Hanna; Kaczorowski, Catherine C.; Helmstetter, Fred J.; Furtmüller, Roman; Ecker, Gerhard F.; Parker, Michael W.; Sieghart, Werner; Cook, James M.

doi:10.2174/092986707782360097

Cited by 63 publications

(99 citation statements)

References 103 publications

(119 reference statements)

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“…A novel approach to achieve this goal was developed by Cook and coworkers in the 1980s (1,25) that employed a pharmacophore/receptor model based on the binding affinity of rigid ligands to BDZ/GABA A receptor sites (8). From this series of receptor models for ␣ 1-6 ␤3␥2 subtypes a robust pharmacophore for ␣5-subtype selective ligands emerged resulting in the synthesis of a novel ␣5␤3␥2 partial agonist modulator: (R)-ethyl 8-ethynyl-6-(2-fluorophenyl)-4-methyl-4H-benzo[f]imidazo [1,5-a] [1,4]diazepine-3-carboxylate (or SH-053-2=-F-R-CH 3 ) (10).…”

mentioning

confidence: 99%

Selective targeting of the α5-subunit of GABA_A receptors relaxes airway smooth muscle and inhibits cellular calcium handling

Gallos

Yocum

Siviski

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Selective targeting of the ␣5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling. Am J Physiol Lung Cell Mol Physiol 308: L931-L942, 2015. First published February 6, 2015 doi:10.1152/ajplung.00107.2014The clinical need for novel bronchodilators for the treatment of bronchoconstrictive diseases remains a major medical issue. Modulation of airway smooth muscle (ASM) chloride via GABA A receptor activation to achieve relaxation of precontracted ASM represents a potentially beneficial therapeutic option. Since human ASM GABAA receptors express only the ␣4-and ␣5-subunits, there is an opportunity to selectively target ASM GABAA receptors to improve drug efficacy and minimize side effects. Recently, a novel compound (R)-) with allosteric selectivity for ␣5-subunit containing GABAA receptors has become available. We questioned whether this novel GABAA ␣5-selective ligand relaxes ASM and affects intracellular calcium concentration ([Ca 2ϩ ]i) regulation. Immunohistochemical staining localized the GABAA ␣5-subunit to human ASM. The selective GABAA ␣5 ligand SH-053-2=F-R-CH3 relaxes precontracted intact ASM; increases GABA-activated chloride currents in human ASM cells in voltage-clamp electrophysiology studies; and attenuates bradykinin-induced increases in [Ca 2ϩ ]i, store-operated Ca 2ϩ entry, and methacholine-induced Ca 2ϩ oscillations in peripheral murine lung slices. In conclusion, selective subunit targeting of endogenous ␣5-subunit containing GABAA receptors on ASM may represent a novel therapeutic option to treat severe bronchospasm.GABAA ␣5-subunit; SH-053-2=F-R-CH3; airway relaxation DESPITE A PRESSING CLINICAL need for novel bronchodilators in the treatment of asthma and other bronchoconstrictive diseases, only three drug classes are currently in clinical use as acute bronchodilators in the United States (methylxanthines, anticholinergics, and ␤-adrenoceptor agonists) (6). An emerging novel pathway to achieve bronchodilation involves modulating airway smooth muscle (ASM) chloride conductance via GABA A receptors to achieve relaxation of human precontracted ASM (15). Although there is legitimate concern that widespread activation of all GABA A receptors may lead to undesirable side effects (sedation, hypnosis, etc.), we have shown that human ASM cells express a limited repertoire of GABA A receptor subunits, with the ␣4-and ␣5-subunits the only ␣-subunits expressed, thereby allowing for potential selective pharmacological tissue specific receptor targeting to minimize side effects (18,33). Inhaled delivery of these selective compounds may also serve to obviate concerns of systemic effects. Concern regarding nonselective GABA A receptor activation is not limited to the airway. GABA A receptor ligands active in the central nervous system (CNS) can have many effects including anxiolytic, sedative, hypnotic, amnesic, anticonvulsant, and muscle relaxant effects. This motivated a search for benzodiazepine (BDZ) ligands that discriminate among the ␣-subunits of ...

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mentioning

confidence: 99%

Selective targeting of the α5-subunit of GABA_A receptors relaxes airway smooth muscle and inhibits cellular calcium handling

Gallos

Yocum

Siviski

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Previously, evidence from the ligand-based GABA A R pharmacophore/receptor model and SAR 23,35 have indicated that subtle changes in the IBZD substituents affect the BzR/GABA(A)R subtype selectivity dramatically. For instance, loss of the methyl group at the C(4) position decreases the α5-subtype efficacy while the efficacy at α2/α3-β3γ2 GABA(A)ergic subtypes increases dramatically.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression

Li¹,

Rajesh²,

Kodali³

et al. 2018

Arkivoc

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A series of novel imidazobenzodiazepine analogs of the lead chiral ligand SH-053-2'F-S-CH 3 (2), an α2/α3/α5 (Bz)GABA (A)ergic receptor subtype selective ligand, which reverses PCP-induced prepulse inhibition (PPI) of acoustic startle, were synthesized. These chiral (S)-CH 3 ligands are targeted for the treatment of schizophrenia and depression. These new ligands were designed by modifying the labile ester functionality in 2 to improve the metabolic stability, cytotoxicity, and activity as compared to 2. Based on the data to date, the most promising ligands are the N-cyclopropyl amide GL-I-55 (8c) and the methyl bioisostere GL-I-65 (9a). The in vitro metabolic stability, cytotoxicity and in vivo locomotor effects are described in this report. Based on these results, 8c and 9a are the most promising for further in vivo pharmacology.

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“…The effect of the ligand-receptor reaction is the opening of chloride channels and hyperpolarisation of the nervous membrane, leading to the clinical effects of anaesthesia, amnesia and anxiolysis . Barbiturates prolong the time of ion channel opening (initiated earlier by benzodiazepines) via synergism [28].…”

Section: Mechanisms Of the Neurotoxicity Of Anaestheticsmentioning

confidence: 99%

Czy rzeczywiście znany jest efekt farmakodynamiczny środków stosowanych podczas znieczulenia ogólnego u noworodków, niemowląt i dzieci? Przegląd eksperymentalnych i klinicznych badań dotyczących działania neurodegeneracyjnego

Bartkowska-Śniatkowska

Rosada-Kurasińska²,

Zielińska³

et al. 2014

Anaesthesiol Intensive Ther

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The practices of anaesthesiology and intensive therapy are difficult to imagine without sedation or general anaesthesia, regardless of whether the patient is a newborn, baby, child or adult. The relevant concerns for children are distinct from those for adults, primarily due to the effects of anatomical, physiological and pharmacokinetic-pharmacodynamic (PK/PD) differences, which become increasingly important in the brains of children as they develop. The process of central nervous system maturation in humans lasts for years, but its greatest activity (myelination and synaptogenesis) occurs during the fetal period and the first two years of life. Many experimental studies have demonstrated that exposure to anaesthetic drugs during this period can induce neurodegenerative changes in the central nervous systems of animals. The extrapolation of these results directly to humans must be performed with great caution, but anaesthesiologists around the world must begin to debate the safety of general anaesthesia in humans. Prospective trials should continue being carried out, and anaesthesia and surgery, delayed if possible among the smallest patients. The simultaneous use of different anaesthetics with the same potential neurotoxicities should also be avoided, potentially in favour of regional anaesthesia techniques, in this group of patients.

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An Updated Unified Pharmacophore Model of the Benzodiazepine Binding Site on γ-Aminobutyric Acida Receptors: Correlation with Comparative Models

Cited by 63 publications

References 103 publications

Selective targeting of the α5-subunit of GABA_A receptors relaxes airway smooth muscle and inhibits cellular calcium handling

Selective targeting of the α5-subunit of GABA_A receptors relaxes airway smooth muscle and inhibits cellular calcium handling

Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression

Czy rzeczywiście znany jest efekt farmakodynamiczny środków stosowanych podczas znieczulenia ogólnego u noworodków, niemowląt i dzieci? Przegląd eksperymentalnych i klinicznych badań dotyczących działania neurodegeneracyjnego

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An Updated Unified Pharmacophore Model of the Benzodiazepine Binding Site on &#947;-Aminobutyric Acida Receptors: Correlation with Comparative Models

Cited by 63 publications

References 103 publications

Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling

Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling

Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression

Czy rzeczywiście znany jest efekt farmakodynamiczny środków stosowanych podczas znieczulenia ogólnego u noworodków, niemowląt i dzieci? Przegląd eksperymentalnych i klinicznych badań dotyczących działania neurodegeneracyjnego

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An Updated Unified Pharmacophore Model of the Benzodiazepine Binding Site on γ-Aminobutyric Acida Receptors: Correlation with Comparative Models

Selective targeting of the α5-subunit of GABA_A receptors relaxes airway smooth muscle and inhibits cellular calcium handling

Selective targeting of the α5-subunit of GABA_A receptors relaxes airway smooth muscle and inhibits cellular calcium handling