Differential inhibition of rat α3* and α7 nicotinic acetylcholine receptors by tetrandrine and closely related bis-benzylisoquinoline derivatives

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 α 3-containing nAChR (α 3*nAChR) endogenously expressed in PC 12 cells and the rat α 7-nAChR heterologously expressed in GH4C1 cells. Tetrandrine and hernandezine reversibly inhibited both receptors displaying half-maximal inhibitory concentrations (IC50) of 8.1 μ M and 5.8 μ M for α 3*nAChR and 407.4 nM and 372.2 nM, respectively, for α 7-nAChR. E-6-berbamine completely inhibited the α 3*nAChR with an IC50 of 5.1 μ M, but only partially inhibited the α 7-nAChR at concentrations up to 30 μ M. Tetrandrine inhibition of α 3*nAChR was functionally non- competitive. All three compounds displaced radiolabelled methyllycaconitine, ([H-3]-MLA) binding to α 7-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 α 7 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. © 2005 Elsevier Ireland Ltd. All rights reserved.