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Bodenstein J.Pdf B. Pharm., Hons, B.Sc. (Pharmaco/ogy), MA. (Pharmacology) Thesis submitted for the degree: Philosophiae Dodor in: Pharmacology at the: Potchektroomse Universiteit vir Christelike H&r 0nderwy.s Promoter: Prof CB. Brink Co-promoter: Prof D.P. Venter Potchefstroom August 2003 Title: Antagonism by selected classical irreversible competitive antagonistr: An investigation into the proposed non-specific mechanisms involved Many irreversible antagonists are known to bind irreversibly to pharmacological receptors. However, few studies suggest that these irreversible antagonists may also display irreversible non-specific antagonism by binding irreversibly to non-syntopic binding sites on the receptor macromolecule, whereby they modulate the signal transduction of these receptors or reduce the agonist binding affmity. The aim of this study was to investigate whether the classical irreversible antagonists phenoxybenzamine, benextramine and 4-DAMP mustard display irreversible non- specific antagonism at various G protein-coupled receptor (GPCR) types. In addition, the subcellular mechanism whereby benextramine displays irreversible non-specific antagonism was investigated. Three cell lines were employed to investigate the antagonism by these irreversible antagonists: Chinese hamster ovary (CHO-K1) cells transfected to express the porcine %A-adrenoceptor (u~A-AR)at higher (u~A-H)or lower (azA-L) numbers, human neuroblastoma (SH-SYSY) cells that endogenously express muscarinic acetylcholine receptors (mACh-Rs), and SH-SYSY cells transfected (SHT~A-SH-SYSY)to express the human SHT~A-serotoninreceptor (SHTZA-R).Cells of the appropriate cell line were pre-treated at the appropriate concentrations and incubation times with an appropriate irreversible antagonist, with or without an appropriate reversible competitive antagonist at a sufficient concentration to protect the specific receptors. This was followed by washing procedures with drug-free media to rinse any unbound or reversibly bound drugs from the cells. When appropriate, cell membranes were prepared. Receptor function was evaluated by measuring wbole-cell ['HI-CAMP or [3~]-~~,accumulation, or the binding of [35~]-~~~y~to membranes. Receptor concentrations were determined from radioligand-binding assays. In addition, the constitutive [35~]-~~~~ binding to Go protein before and after pre-treatment with benextramine was investigated. Results suggest that phenoxybenzamine (100 pM, 20 minutes) and benextramine (10 pM, 20 minutes) display irreversible non-specific antagonism at a2~-ARswhen measuring G,-mediated effects in a2~-Lcells, but the affinity for a2~-ARsin a2~-H cells was not changed. In addition, it was found that the observed irreversible non- specific antagonism by benextramine appears to be time- and concentration-dependent. When the mechanism of irreversible antagonism by benextramine was further investigated, benextramine reduced the binding of [35~]-~~F'y~to a2~-H membranes with protected a2~-ARS,but did not modulate the constitutive binding of [35~]-~~~y~ to Go. In addition, benextramine displays irreversible non-specific antagonism by inhibiting the G,-mediated effects of a2~-ARsin azA-H cells and the G,-mediated effects of dch-Rs or ~HT~A-Rsin SH-SY5Y or 5HT2A-SH-SY5Ycells respectively. 4-DAMP mustard (100 nM, 20 minutes) did not display irreversible non-specific antagonism at mACh-Rs in SH-SYSY cells, but irreversible non-specific antagonism was observed when the incubation time was increased (100 nM, 60 minutes). In conclusion it was found that phenoxybenzamine, benextramine and 4-DAMP mustard display irreversible non-specific antagonism at typical experimental conditions. These findings confirm concerns in literature and supports the possibility that more irreversible antagonists could display irreversible non-specific antagonism, and that could influence the interpretation of data obtained with such drugs. In addition, benextramine may prove to be a useful experimental drug in studying GPCR signalling. Keywords: 4-DAMP mustard; 5HTa-serotonin receptor; aa -adrenoceptor; benewtratnine; G protein-coupled receptor; irreve~ibleantagonist; rnuscarinic acetylcoline receptor; non-syntopic binding site; phenoxybenzarnine; s,fic receptor. Titel: Antagonisme deurgeselekeerde klassieke onomkeerbare kompeterende antagoniste: ?I Ondersok na die voorgestelde non-spesifieke meganismes . betrokke Talle onomkeerbare antagoniste is bekend daarvoor dat hulle onomkeerbaar aan fmakologiese reseptore bind. 'n Paar studies suggereer egter dat hierdie onomkeerbare antagoniste ook onomkeerbare non-spesifieke antagonisme mag openbaar deur onomkeerbaar aan non-sintopiese bindingsetels van die reseptormakromolekule te bind, en daardeur die seingeleiding van hierdie reseptore moduleer of agonisbindingsaffiniteit verlaag. Die doe1 van hierdie studie was om ondersoek in te stel of die klassieke onomkeerbare antagoniste fenoksibensamien, benekstramien en 4-DAMP mosterd onomkeerbare non-spesifieke antagonisme by verskeie tipes G-proteyengekoppelde reseptore openbaar. Daarby is die subsellul6re meganisme waardeur benekstramien onomkeerbare non-spesifieke antagonisme openbaar, ondersoek. Drie sellyne is gebruik om die antagonisme deur hierdie onomkeerbare antagoniste te ondersoek: Ovariumselle van die Chinese hamster (CHO-K1) getransfekteer om die az~-adrenoseptor(~~A-AR) van die vark in hoisr (a2~-H)of laer (a2~-L)hoeveelhede uit te druk, menslike neuroblastoomselle (SH-SY5Y) wat endogene muskariniese asetielcholiemeseptore (mACh-R'e) uitdruk, en SH-SY5Y-selle getransfekteer (5HT2~- SH-SY5Y) om die menslike 5HT2~-serotoniemeseptor(~HT~A-R) uit te druk. Selle van die toepaslike sellyn is vooraf teen die toepaslike konsentrasies en inkubasietye met 'n toepaslike onomkeerbare antagonis behandel, met of sonder 'n toepaslike omkeerhare kompeterende antagonis in 'n voldoende konsentrasie om spesifieke reseptore te beskerm. Dit is opgevolg dew wasprosedures met geneesmiddelvrye media om enige ongebonde of omkeerbaar-gebonde geneesmiddels van die selle te spoel. Selmembrane is waar toepaslik berei. Reseptorfunksie is geisvalueer deur die akkumulasie van ['HI- CAMP of ['HI-IP, in heelselle of die binding van [35~]-~~~~aan membrane te meet. Reseptorkonsentrasies is dew radioligandbindingstudies bepaal. Die binding van [35~]- GTPyS aan Go-protei'en in die afwesigheid van 'n agonis voor en na behandeling met benekstramien is ook ondersoek. Resultate verkry dew Gi-gemedieerde effekte in azA-L-selle te meet suggereer dat fenoksibensarnien (100 pM, 20 minute) en benekstramien (10 pM, 20 minute) onomkeerbare non-spesifieke antagonisme by az~-AR'e openbaar, maar nie die afiniteit vir azA-AR1ein azA-H-selle verander nie. Dit wil ook voorkom asof die waargenome onomkeerbare non-spesifieke antagonisme dew benekstramien tyd- en konsentrasie-afhanklik is. Toe die meganisme van onomkeerbare antagonisme deur benekstramien verder ondersoek is, is gevind dat benekstramien die binding van [35~]- GTPyS aan a2~-Hmembrane met beskermde az~-AR'everminder het, maarnie die binding van [35~]-~~Py~aan Go in die afwesigheid van 'n agonis nie. Dit is ook gevind dat benekstramien onomkeerbare non-spesifieke antagonisme openbaar dew die G,- gemedieerde effekte van ~ZA-AR'ein a2~-H-selleen die G,-gemedieerde effekte van mACh-R'e of SHT2A-R'e in SH-SYSY- of SHT~A-SH-SYSY-sellerespektiewelik te verlaag. 4-DAMP mosterd (100 nh4, 20 minute) het nie onomkeerbare non-spesifieke antagonisme by mACh-R'e in SH-SYSY-selle openbaar nie, maar onomkeerbare non- spesifieke antagonisme is waargeneem toe die inkubasietyd verleng is (100 nh4, 60 minute). Dit is dus gevind dat fenoksibensamien, benekstramien en 4-DAMP mosterd onder tipiese eksperimentele toestande onomkeerbare non-spesifieke antagonisme openbaar. Hierdie bevindinge bevestig die besorgdhede in die literatuur en ondersteun die moontlikheid dat meer onomkeerbare antagoniste ook onomkeerbare non-spesifieke antagonisme kan openbaar, en dit kan die interpretasie van data bei'nvloed wat met hierdie geneesmiddels verkry is. Benekstramien mag ook nuttig wees as 'n eksperimentele geneesmiddel om seingeleiding in G-protei'engekoppelde reseptore te bestudeer. Skutehvoorde: 4-DAMP mosterd; 5HTa -serotonienres@oc an - adrenoseptor; benekstramien; fenoksibensamien; ~-~tvtefen~eko~~e/de reseptor; muskariniese asetielcholienreseptor; non-sintopiese bindingseteb onomkeerbare antagonis. Abstract ...............................................................................................i ... Opsomming .........................................................................................111 Table of Figures .................................. ................................................x Table of Tables .................................................................................xv Preface ..............................................................................................xvi Format of this thesis................................................................................................... xvi Participation of authors in articles ................................................................................ xvii Approval for submission............................................................................................... xx Chapter 1: Introduction .......................................................................1 1.1 Problem statement .................................................................................................. 1 1.2 Study objectives ......................................................................................................5
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