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Open AccessFeature PaperArticle

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

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, USA
3
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)
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. View Full-Text
Keywords: opioid receptor; imidazodiazepine; GABAA receptor opioid receptor; imidazodiazepine; GABAA receptor
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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 GABAA Receptor. Molecules 2020, 25, 3864.

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 GABAA Receptor. Molecules. 2020; 25(17):3864.

Chicago/Turabian Style

Li, Guanguan; Nieman, Amanda N.; Mian, Md Y.; Zahn, Nicolas M.; Mikulsky, Brandon N.; Poe, Michael M.; Methuku, Kashi R.; Liu, Yongfeng; Cook, James M.; Stafford, Douglas C.; 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, no. 17: 3864.

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