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Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT 3 ) Subunit A Receptors
Journal article   Peer reviewed

Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT 3 ) Subunit A Receptors

Katie Alix, Shailesh Khatri, Philip D Mosier, Samantha Casterlow, Dong Yan, Heather L Nyce, Michael M White, Marvin K Schulte and Małgorzata Dukat
ACS chemical neuroscience, v 7(11), pp 1565-1574
16 Nov 2016
DOI: https://doi.org/10.1021/acschemneuro.6b00196
PMID: 27533595
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

Animals Cell Line, Tumor Dose-Response Relationship, Drug Guanidines - chemical synthesis Guanidines - chemistry Guanidines - pharmacology HEK293 Cells Humans Membrane Potentials - drug effects Membrane Potentials - physiology Mice Models, Molecular Molecular Structure Mutation Oocytes Protein Binding Receptors, Serotonin, 5-HT3 - genetics Receptors, Serotonin, 5-HT3 - metabolism Serotonin 5-HT3 Receptor Agonists - chemical synthesis Serotonin 5-HT3 Receptor Agonists - chemistry Serotonin 5-HT3 Receptor Agonists - pharmacology Serotonin 5-HT3 Receptor Antagonists - chemical synthesis Serotonin 5-HT3 Receptor Antagonists - chemistry Serotonin 5-HT3 Receptor Antagonists - pharmacology Xenopus
Introduction of minor variations to the substitution pattern of arylguanidine 5-hydroxytryptamine-3 (5-HT ) receptor ligands resulted in a broad spectrum of functionally-active ligands from antagonist to superagonist. For example, (i) introduction of an additional Cl-substituent(s) to our lead full agonist N-(3-chlorophenyl)guanidine (mCPG, 2; efficacy % = 106) yielded superagonists 7-9 (efficacy % = 186, 139, and 129, respectively), (ii) a positional isomer of 2, p-Cl analog 11, displayed partial agonist actions (efficacy % = 12), and (iii) replacing the halogen atom at the meta or para position with an electron donating OCH group or a stronger electron withdrawing (i.e., CF ) group resulted in antagonists 13-16. We posit based on combined mutagenesis, crystallographic, and computational analyses that for the 5-HT receptor, the arylguanidines that are better able to simultaneously engage the primary and complementary subunits, thus keeping them in close proximity, have greater agonist character while those that are deficient in this ability are antagonists.

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Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
Chemistry, Medicinal
Neurosciences
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