Synthetic and computer assisted analysis of the pharmacophore for agonists at benzodiazepine receptors

Diaz-Arauzo, Hernando; Koehler, Konrad F.; Hagen, Timothy J.; Cook, James M.

doi:10.1016/0024-3205(91)90005-v

Cited by 65 publications

(84 citation statements)

References 27 publications

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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%

“…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). Given that ␣4-and ␣5-subunit-containing GABA A receptors are known to be present on ASM cells, it was of interest to examine the effects of this ␣5 BDZ/GABAergic subtype-selective agonist on ASM function and cellular signaling.…”

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confidence: 99%

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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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confidence: 99%

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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“…The general aim of our project is structure-activity correlations. Since these correlations can be based on structural and electronic parameters derived from a geometrical description of the molecule (Konschin, Tylli, Gynther & Rouvinen, 1989;Diaz-Arauzo, Koehler, Hagen & Cook, 1991), the three-dimensional structures and…”

Section: Commentmentioning

confidence: 99%

(Z)-1-Ethyl-3-(4-chlorobenzylidene)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazoline-2,5-dione

Karolak‐Wojciechowska¹,

Kieć‐Kononowicz²

1995

Acta Crystallogr C

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The central part of the title molecule, C19H14C1N302, The main skeleton of the molecule (three condensed 7r-electron rings inclined slightly towards one another) and the phenyl ring have a Z configuration with torsion angle N1---C5---C6--C16 = -8.5 (9) °. Thus, as a result of steric hindrance, the imidazo-quinazolinedione skeleton and the phenyl ring are not coplanar, and form a dihedral angle of 48.1 (1)°.

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“…TWO ISOMERS OF C19HlsF3N40 Doble & Martin, 1992;Borea, Gilli, Bertolasi & Ferretti, 1986) and constitute an interesting subject for studying the correlation between structure and affinity to the receptor (Karolak-Wojciechowska, Lange, Kwiatkowski, Gniewosz & Plenkiewicz, 1994). Since the structureactivity correlations can be based on structural and electronic parameters derived from a geometrical description of the molecule (Konschin, Tylli, Gynther & Rouvinen, 1989;Diaz-Arauzo, Koehler, Hagen & Cook, 1991), the three-dimensional structures and conformations of all investigated molecules have to be determined. The geometry of the basic triazolo [4,3-b]pyridazine ring system (Ill), which is aromatic and therefore planar, is well known from crystallographic data (Bertolasi, Ferretti, Gilli & Borea, 1990;Boulanger, Ledent, Vercauteren, Norberg, Evrard & Durant, 1988;Goli6, Leban, Stanovnik & Tiller, 1977, 1978Boulanger, Ledent, Norberg, Vercauteren, Evrard & Durant, 1989;Larson, Yoghan Kang, Revankar & Robins, 1989), but no structures with a partially hydrogenated pyridazine ring [as in (I) (Lange, KarolakWojciechowska, Gniewosz & Plenkiewicz, 1994).…”

Section: S Deviation (~) For This Planementioning

confidence: 99%

Bicyclic [b]-Heteroannulated Pyridazine Derivatives. 3. Partially Hydrogenated Triazolo[4,3-b]pyridazines

Karolak‐Wojciechowska¹,

Trzezwinska²,

Lange³

et al. 1995

Acta Crystallogr C

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The structures of 6-benzyloxy-7,8-dihydro-8-phenyl-3-trifluoromethyl-s-triazolo[4,3-b]pyridazine, (1), and its isomer, 5-benzyl-5,6,7,8-tetrahydro-8-phenyl-3-trifluoromethyl-s-triazolo[4,3-b]pyridazin-6-one, (2), C19HI5F3-N40, have been solved. The two molecules differ in the bonding at N5 and in the conformation of the pyridazine ring which contains this atom. This partially hydrogenated six-membered ring is puckered in both molecules, adopting a half-chair shape in (1) and a twistboat shape in (2). In both molecules, the triazole ring and the mean plane of the pyridazine ring are not coplanar. CommentMany derivatives of bicyclic [b]-heteroannulated pyridazine are known as compounds of interesting biological activity. In particular, triazolo [4,3-b]pyridazines are classified as ligands of the benzodiazepine receptor with partial agonist activity

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Synthetic and computer assisted analysis of the pharmacophore for agonists at benzodiazepine receptors

Cited by 65 publications

References 27 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

(Z)-1-Ethyl-3-(4-chlorobenzylidene)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazoline-2,5-dione

Bicyclic [b]-Heteroannulated Pyridazine Derivatives. 3. Partially Hydrogenated Triazolo[4,3-b]pyridazines

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Synthetic and computer assisted analysis of the pharmacophore for agonists at benzodiazepine receptors

Cited by 65 publications

References 27 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

(Z)-1-Ethyl-3-(4-chlorobenzylidene)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazoline-2,5-dione

Bicyclic [b]-Heteroannulated Pyridazine Derivatives. 3. Partially Hydrogenated Triazolo[4,3-b]pyridazines

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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