title: Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT3) Subunit A Receptors.
abstract: Introduction of minor variations to the substitution pattern of arylguanidine 5-hydroxytryptamine-3 (5-HT3) 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 OCH3group or a stronger electron withdrawing (i.e., CF3) group resulted in antagonists 13-16. We posit based on combined mutagenesis, crystallographic, and computational analyses that for the 5-HT3receptor, 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Katie
authors.initials: K
authors.lastname: Alix
authors.affiliation: Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of Sciences , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Khatri
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Mosier
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Samantha
authors.initials: S
authors.lastname: Casterlow
authors.affiliation: Department of Biochemistry and Molecular Biology Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Dong
authors.initials: D
authors.lastname: Yan
authors.affiliation: Department of Biochemistry and Molecular Biology Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Nyce
authors.affiliation: Department of Biochemistry and Molecular Biology Drexel University College of Medicine , Philadelphia, Pennsylvania 19102, United States.
authors.forename: Michael M
authors.initials: MM
authors.lastname: White
authors.affiliation: Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of Sciences , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Marvin K
authors.initials: MK
authors.lastname: Schulte
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dukat
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009865:Oocytes; D011485:Protein Binding; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000378:metabolism; D058827:Serotonin 5-HT3 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014981:Xenopus
chemical_list: D006146:Guanidines; C509409:HTR3A protein, human; C511230:Htr3a protein, mouse; D044406:Receptors, Serotonin, 5-HT3; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists
keywords: 3D-graphic models; 5-HT3A receptors; Arylguanidines; SAR; binding affinities; functional activities; site-directed mutagenesis