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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MDPI AG
2020-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/17/3864 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Guanguan Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T16:51:16Z |
| format | Article |
| id | doaj.art-df69adecaff8428ea34ea1acbb5c2c98 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T16:51:16Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-df69adecaff8428ea34ea1acbb5c2c982023-11-20T11:17:51ZengMDPI AGMolecules1420-30492020-08-012517386410.3390/molecules25173864A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub>A</sub> ReceptorGuanguan Li0Amanda N. Nieman1Md Yeunus Mian2Nicolas M. Zahn3Brandon N. Mikulsky4Michael M. Poe5Kashi R. Methuku6Yongfeng Liu7James M. Cook8Douglas C. Stafford9Leggy A. Arnold10Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen 518055, ChinaDepartment of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USADepartment of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USADepartment of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USAPantherics Incorporated, La Jolla, CA 92037, USADepartment of Chemistry, Western Michigan University, Kalamazoo, MI 49008, USADepartment of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USANational Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USADepartment of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USADepartment of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USADepartment of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USAAnalgesic 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.https://www.mdpi.com/1420-3049/25/17/3864opioid receptorimidazodiazepineGABA<sub>A</sub> receptor |
| spellingShingle | 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 A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub>A</sub> Receptor Molecules opioid receptor imidazodiazepine GABA<sub>A</sub> receptor |
| title | A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub>A</sub> Receptor |
| title_full | A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub>A</sub> Receptor |
| title_fullStr | A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub>A</sub> Receptor |
| title_full_unstemmed | A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub>A</sub> Receptor |
| title_short | A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA<sub>A</sub> Receptor |
| title_sort | structure activity relationship comparison of imidazodiazepines binding at kappa mu and delta opioid receptors and the gaba sub a sub receptor |
| topic | opioid receptor imidazodiazepine GABA<sub>A</sub> receptor |
| url | https://www.mdpi.com/1420-3049/25/17/3864 |
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