title: Differential inhibition of rat alpha3* and alpha7 nicotinic acetylcholine receptors by tetrandrine and closely related bis-benzylisoquinoline derivatives.
abstract: The patch-clamp technique was used to investigate the effects of bis-benzylisoquinoline alkaloids on two of the major neuronal nicotinic acetylcholine receptors (nAChRs), the alpha3-containing nAChR (alpha3*nAChR) endogenously expressed in PC12 cells and the rat alpha7-nAChR heterologously expressed in GH4C1 cells. Tetrandrine and hernandezine reversibly inhibited both receptors displaying half-maximal inhibitory concentrations (IC50) of 8.1 microM and 5.8 microM for alpha3*nAChR and 407.4 nM and 372.2 nM, respectively, for alpha7-nAChR. E6-berbamine completely inhibited the alpha3*nAChR with an IC50 of 5.1 microM, but only partially inhibited the alpha7-nAChR at concentrations up to 30 microM. Tetrandrine inhibition of alpha3*nAChR was functionally non-competitive. All three compounds displaced radiolabelled methyllycaconitine ([3H]-MLA) binding to alpha7-nAChR providing some evidence of competitive antagonism. The results demonstrate that these alkaloids are nAChRs antagonists, with tetrandrine and hernandezine displaying selectivity for one of the major neuronal subtype, the alpha7 nAChR. The different potencies and multiple modes of action on nAChRs may help to better understand the pharmacology of these receptors and to aid in novel drug design.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Assay Development and Compound Profiling, Via A. Fleming 4, 37135 Verona, Italy. caterina.s.virginio@gsk.com
authors.forename: Caterina
authors.initials: C
authors.lastname: Virginio
authors.forename: Francesca
authors.initials: F
authors.lastname: Graziani
authors.forename: Georg C
authors.initials: GC
authors.lastname: Terstappen
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D044182:Benzylisoquinolines / Q000494:pharmacology*; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000470:Alkaloids; D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579165:Chrna7 protein, rat; C009438:tetrandrine