A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor

Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opio...
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Autor*in:	Guanguan Li [verfasserIn] Amanda N. Nieman [verfasserIn] Md Yeunus Mian [verfasserIn] Nicolas M. Zahn [verfasserIn] Brandon N. Mikulsky [verfasserIn] Michael M. Poe [verfasserIn] Kashi R. Methuku [verfasserIn] Yongfeng Liu [verfasserIn] James M. Cook [verfasserIn] Douglas C. Stafford [verfasserIn] Leggy A. Arnold [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	opioid receptor imidazodiazepine GABA

Übergeordnetes Werk:	In: Molecules - MDPI AG, 2003, 25(2020), 17, p 3864
Übergeordnetes Werk:	volume:25 ; year:2020 ; number:17, p 3864

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/molecules25173864

Katalog-ID:	DOAJ038967871

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allfields	10.3390/molecules25173864 doi (DE-627)DOAJ038967871 (DE-599)DOAJdf69adecaff8428ea34ea1acbb5c2c98 DE-627 ger DE-627 rakwb eng QD241-441 Guanguan Li verfasserin aut A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC<sub<50</sub< of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with <sup<3</sup<H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABA<sub<A</sub<R) of the α<sub<1-3</sub<β<sub<2-3</sub<γ<sub<1-2</sub< subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABA<sub<A</sub<Rs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors. opioid receptor imidazodiazepine GABA<sub<A</sub< receptor Organic chemistry Amanda N. Nieman verfasserin aut Md Yeunus Mian verfasserin aut Nicolas M. Zahn verfasserin aut Brandon N. Mikulsky verfasserin aut Michael M. Poe verfasserin aut Kashi R. Methuku verfasserin aut Yongfeng Liu verfasserin aut James M. Cook verfasserin aut Douglas C. Stafford verfasserin aut Leggy A. Arnold verfasserin aut In Molecules MDPI AG, 2003 25(2020), 17, p 3864 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:25 year:2020 number:17, p 3864 https://doi.org/10.3390/molecules25173864 kostenfrei https://doaj.org/article/df69adecaff8428ea34ea1acbb5c2c98 kostenfrei https://www.mdpi.com/1420-3049/25/17/3864 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2020 17, p 3864
spelling	10.3390/molecules25173864 doi (DE-627)DOAJ038967871 (DE-599)DOAJdf69adecaff8428ea34ea1acbb5c2c98 DE-627 ger DE-627 rakwb eng QD241-441 Guanguan Li verfasserin aut A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC<sub<50</sub< of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with <sup<3</sup<H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABA<sub<A</sub<R) of the α<sub<1-3</sub<β<sub<2-3</sub<γ<sub<1-2</sub< subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABA<sub<A</sub<Rs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors. opioid receptor imidazodiazepine GABA<sub<A</sub< receptor Organic chemistry Amanda N. Nieman verfasserin aut Md Yeunus Mian verfasserin aut Nicolas M. Zahn verfasserin aut Brandon N. Mikulsky verfasserin aut Michael M. Poe verfasserin aut Kashi R. Methuku verfasserin aut Yongfeng Liu verfasserin aut James M. Cook verfasserin aut Douglas C. Stafford verfasserin aut Leggy A. Arnold verfasserin aut In Molecules MDPI AG, 2003 25(2020), 17, p 3864 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:25 year:2020 number:17, p 3864 https://doi.org/10.3390/molecules25173864 kostenfrei https://doaj.org/article/df69adecaff8428ea34ea1acbb5c2c98 kostenfrei https://www.mdpi.com/1420-3049/25/17/3864 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2020 17, p 3864
allfields_unstemmed	10.3390/molecules25173864 doi (DE-627)DOAJ038967871 (DE-599)DOAJdf69adecaff8428ea34ea1acbb5c2c98 DE-627 ger DE-627 rakwb eng QD241-441 Guanguan Li verfasserin aut A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC<sub<50</sub< of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with <sup<3</sup<H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABA<sub<A</sub<R) of the α<sub<1-3</sub<β<sub<2-3</sub<γ<sub<1-2</sub< subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABA<sub<A</sub<Rs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors. opioid receptor imidazodiazepine GABA<sub<A</sub< receptor Organic chemistry Amanda N. Nieman verfasserin aut Md Yeunus Mian verfasserin aut Nicolas M. Zahn verfasserin aut Brandon N. Mikulsky verfasserin aut Michael M. Poe verfasserin aut Kashi R. Methuku verfasserin aut Yongfeng Liu verfasserin aut James M. Cook verfasserin aut Douglas C. Stafford verfasserin aut Leggy A. Arnold verfasserin aut In Molecules MDPI AG, 2003 25(2020), 17, p 3864 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:25 year:2020 number:17, p 3864 https://doi.org/10.3390/molecules25173864 kostenfrei https://doaj.org/article/df69adecaff8428ea34ea1acbb5c2c98 kostenfrei https://www.mdpi.com/1420-3049/25/17/3864 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2020 17, p 3864
allfieldsGer	10.3390/molecules25173864 doi (DE-627)DOAJ038967871 (DE-599)DOAJdf69adecaff8428ea34ea1acbb5c2c98 DE-627 ger DE-627 rakwb eng QD241-441 Guanguan Li verfasserin aut A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC<sub<50</sub< of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with <sup<3</sup<H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABA<sub<A</sub<R) of the α<sub<1-3</sub<β<sub<2-3</sub<γ<sub<1-2</sub< subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABA<sub<A</sub<Rs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors. opioid receptor imidazodiazepine GABA<sub<A</sub< receptor Organic chemistry Amanda N. Nieman verfasserin aut Md Yeunus Mian verfasserin aut Nicolas M. Zahn verfasserin aut Brandon N. Mikulsky verfasserin aut Michael M. Poe verfasserin aut Kashi R. Methuku verfasserin aut Yongfeng Liu verfasserin aut James M. Cook verfasserin aut Douglas C. Stafford verfasserin aut Leggy A. Arnold verfasserin aut In Molecules MDPI AG, 2003 25(2020), 17, p 3864 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:25 year:2020 number:17, p 3864 https://doi.org/10.3390/molecules25173864 kostenfrei https://doaj.org/article/df69adecaff8428ea34ea1acbb5c2c98 kostenfrei https://www.mdpi.com/1420-3049/25/17/3864 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2020 17, p 3864
allfieldsSound	10.3390/molecules25173864 doi (DE-627)DOAJ038967871 (DE-599)DOAJdf69adecaff8428ea34ea1acbb5c2c98 DE-627 ger DE-627 rakwb eng QD241-441 Guanguan Li verfasserin aut A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC<sub<50</sub< of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with <sup<3</sup<H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABA<sub<A</sub<R) of the α<sub<1-3</sub<β<sub<2-3</sub<γ<sub<1-2</sub< subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABA<sub<A</sub<Rs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors. opioid receptor imidazodiazepine GABA<sub<A</sub< receptor Organic chemistry Amanda N. Nieman verfasserin aut Md Yeunus Mian verfasserin aut Nicolas M. Zahn verfasserin aut Brandon N. Mikulsky verfasserin aut Michael M. Poe verfasserin aut Kashi R. Methuku verfasserin aut Yongfeng Liu verfasserin aut James M. Cook verfasserin aut Douglas C. Stafford verfasserin aut Leggy A. Arnold verfasserin aut In Molecules MDPI AG, 2003 25(2020), 17, p 3864 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:25 year:2020 number:17, p 3864 https://doi.org/10.3390/molecules25173864 kostenfrei https://doaj.org/article/df69adecaff8428ea34ea1acbb5c2c98 kostenfrei https://www.mdpi.com/1420-3049/25/17/3864 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2020 17, p 3864
language	English
source	In Molecules 25(2020), 17, p 3864 volume:25 year:2020 number:17, p 3864
sourceStr	In Molecules 25(2020), 17, p 3864 volume:25 year:2020 number:17, p 3864
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	opioid receptor imidazodiazepine GABA<sub<A</sub< receptor Organic chemistry
isfreeaccess_bool	true
container_title	Molecules
authorswithroles_txt_mv	Guanguan Li @@aut@@ Amanda N. Nieman @@aut@@ Md Yeunus Mian @@aut@@ Nicolas M. Zahn @@aut@@ Brandon N. Mikulsky @@aut@@ Michael M. Poe @@aut@@ Kashi R. Methuku @@aut@@ Yongfeng Liu @@aut@@ James M. Cook @@aut@@ Douglas C. Stafford @@aut@@ Leggy A. Arnold @@aut@@
publishDateDaySort_date	2020-01-01T00:00:00Z
hierarchy_top_id	311313132
id	DOAJ038967871
language_de	englisch
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callnumber-first	Q - Science
author	Guanguan Li
spellingShingle	Guanguan Li misc QD241-441 misc opioid receptor misc imidazodiazepine misc GABA<sub<A</sub< receptor misc Organic chemistry A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor
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topic_title	QD241-441 A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor opioid receptor imidazodiazepine GABA<sub<A</sub< receptor
topic	misc QD241-441 misc opioid receptor misc imidazodiazepine misc GABA<sub<A</sub< receptor misc Organic chemistry
topic_unstemmed	misc QD241-441 misc opioid receptor misc imidazodiazepine misc GABA<sub<A</sub< receptor misc Organic chemistry
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title	A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor
ctrlnum	(DE-627)DOAJ038967871 (DE-599)DOAJdf69adecaff8428ea34ea1acbb5c2c98
title_full	A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor
author_sort	Guanguan Li
journal	Molecules
journalStr	Molecules
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author_browse	Guanguan Li Amanda N. Nieman Md Yeunus Mian Nicolas M. Zahn Brandon N. Mikulsky Michael M. Poe Kashi R. Methuku Yongfeng Liu James M. Cook Douglas C. Stafford Leggy A. Arnold
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title_sort	structure-activity relationship comparison of imidazodiazepines binding at kappa, mu, and delta opioid receptors and the gaba<sub<a</sub< receptor
callnumber	QD241-441
title_auth	A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor
abstract	Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC<sub<50</sub< of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with <sup<3</sup<H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABA<sub<A</sub<R) of the α<sub<1-3</sub<β<sub<2-3</sub<γ<sub<1-2</sub< subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABA<sub<A</sub<Rs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors.
abstractGer	Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC<sub<50</sub< of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with <sup<3</sup<H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABA<sub<A</sub<R) of the α<sub<1-3</sub<β<sub<2-3</sub<γ<sub<1-2</sub< subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABA<sub<A</sub<Rs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors.
abstract_unstemmed	Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC<sub<50</sub< of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with <sup<3</sup<H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABA<sub<A</sub<R) of the α<sub<1-3</sub<β<sub<2-3</sub<γ<sub<1-2</sub< subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABA<sub<A</sub<Rs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors.
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container_issue	17, p 3864
title_short	A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor
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author2	Amanda N. Nieman Md Yeunus Mian Nicolas M. Zahn Brandon N. Mikulsky Michael M. Poe Kashi R. Methuku Yongfeng Liu James M. Cook Douglas C. Stafford Leggy A. Arnold
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score	7.399805

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A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub<A</sub< Receptor

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