A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor

Li，Guanguan1; Nieman，Amanda N.2; Mian，Md Yeunus2; Zahn，Nicolas M.2; Mikulsky，Brandon N.3; Poe，Michael M.4; Methuku，Kashi R.2; Liu，Yongfeng5; Cook，James M.2; Stafford，Douglas C.2,3; Arnold，Leggy A.2,3

2020-08-25

10.3390/molecules25173864

MOLECULES   影响因子和分区

1420-3049

1420-3049

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 EC50 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 3H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABAAR) of the α1-3β2-3γ1-2 subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABAARs. 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.

GABAA receptor imidazodiazepine opioid receptor

SCI

英语

第一

National Institutes of Health (USA)[R41HL147658][R01NS076517][R01HL118561] ; National Science Foundation, Division of Chemistry[CHE-1625735]

Biochemistry & Molecular Biology ; Chemistry

Biochemistry & Molecular Biology ; Chemistry, Multidisciplinary

WOS:000569709700001

MDPI

CHEMISTRY

2-s2.0-85090013186

Scopus

1.Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis,Department of Chemistry,College of Science,Southern University of Science and Technology,Shenzhen,518055,China
2.Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery,University of Wisconsin-Milwaukee,Milwaukee,WI 53201,United States
3.
4.Department of Chemistry,Western Michigan University,Kalamazoo,United States
5.National Institute of Mental Health Psychoactive Drug Screening Program,Department of Pharmacology,University of North Carolina Chapel Hill,Chapel Hill,NC 27599,United States

Li，Guanguan,Nieman，Amanda N.,Mian，Md Yeunus,et al. A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor[J]. MOLECULES,2020,25(17).

Li，Guanguan.,Nieman，Amanda N..,Mian，Md Yeunus.,Zahn，Nicolas M..,Mikulsky，Brandon N..,...&Arnold，Leggy A..(2020).A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor.MOLECULES,25(17).

Li，Guanguan,et al."A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor".MOLECULES 25.17(2020).