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 α3-containing nAChR (α3*nAChR) endogenously expressed in PC12 cells and the rat α7-nAChR heterologously expressed in GH4C1 cells. Tetrandrine and hernandezine reversibly inhibited both receptors displaying half-maximal inhibitory concentrations (IC50) of 8.1 μM and 5.8 μM for α3*nAChR and 407.4 nM and 372.2 nM, respectively, for α7-nAChR. E6-berbamine completely inhibited the α3*nAChR with an IC50 of 5.1 μM, but only partially inhibited the α7-nAChR at concentrations up to 30 μM. Tetrandrine inhibition of α3*nAChR was functionally non-competitive. All three compounds displaced radiolabelled methyllycaconitine ([3H]-MLA) binding to α7-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 α7 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.