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

Li, Guanguan; Nieman, Amanda N.; Mian, Md Yeunus; Zahn, Nicolas M.; Mikulsky, Brandon N.; Poe, Michael M.; Methuku, Kashi R.; Liu, Yongfeng; Cook, James M.; Stafford, Douglas C.; Arnold, Leggy A.

doi:10.3390/molecules25173864

Submit to this Journal Review for this Journal Edit a Special Issue

Article Menu

...

Open AccessFeature PaperArticle

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

²,

²,

²,

³,

⁴,

²,

⁵

^2,3 and

^2,3,*

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

Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA

Pantherics Incorporated, La Jolla, CA 92037, USA

⁴

Department of Chemistry, Western Michigan University, Kalamazoo, MI 49008, USA

⁵

National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA

Author to whom correspondence should be addressed.

Academic Editors: Anna Carbone and Josef Jampilek

Molecules 2020, 25(17), 3864; https://doi.org/10.3390/molecules25173864

Received: 21 July 2020 / Revised: 14 August 2020 / Accepted: 23 August 2020 / Published: 25 August 2020

(This article belongs to the Special Issue Nitrogen Heterocycles in Medicinal Chemistry)

View Full-Text Download PDF

Browse Figures

Citation Export

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 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 (GABA_AR) of the α_1-3β_2-3γ_1-2 subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABA_ARs. 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. View Full-Text

Keywords: opioid receptor; imidazodiazepine; GABA_A receptor

▼ Show Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Share and Cite

MDPI and ACS Style

Li, G.; Nieman, A.N.; Mian, M.Y.; Zahn, N.M.; Mikulsky, B.N.; Poe, M.M.; Methuku, K.R.; Liu, Y.; Cook, J.M.; Stafford, D.C.; Arnold, L.A. A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA_A Receptor. Molecules 2020, 25, 3864. https://doi.org/10.3390/molecules25173864

AMA Style

Li G, Nieman AN, Mian MY, Zahn NM, Mikulsky BN, Poe MM, Methuku KR, Liu Y, Cook JM, Stafford DC, Arnold LA. A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA_A Receptor. Molecules. 2020; 25(17):3864. https://doi.org/10.3390/molecules25173864

Chicago/Turabian Style

Li, Guanguan, Amanda N. Nieman, Md Y. Mian, Nicolas M. Zahn, Brandon N. Mikulsky, Michael M. Poe, Kashi R. Methuku, Yongfeng Liu, James M. Cook, Douglas C. Stafford, and Leggy A. Arnold. 2020. "A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABA_A Receptor" Molecules 25, no. 17: 3864. https://doi.org/10.3390/molecules25173864

Find Other Styles

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Metrics

Abstract views Pdf views Html views

Article Menu

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

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Article Access Map by Country/Region

Further Information

Guidelines

MDPI Initiatives

Follow MDPI