Molecular dissection of tropisetron, an α7 nicotinic acetylcholine receptor-selective partial agonist

The 0 nicotinic acetylcholine receptor (nAChR)-selective partial agonist tropisetron is a conjugate of an indole and a tropane group. We tested compounds structurally related to either the indole or tropane domains of tropisetron on oocytes expressing human alpha 7. alpha(4)beta(2), or alpha(3)beta(4) nAChR or rat 5HT(3A) receptors. The simple compounds tropane and tropinone had alpha 7-selective agonist activity comparable to that of tropisetron. Tropinone was more efficacious than tropisetron but 100-fold less potent. Some tropane compounds had antagonist activity on alpha 3 beta 4 nAChR but no effect on alpha(4)beta(2) nAChR. Some tropanes also affected the responses of 5HT3 receptors to serotonin. Tropisetron was more potent at inhibiting alpha(3)beta(4) receptors (IC50 = 1.8 +/- 0.6) than was tropane or tropinone, suggesting that the presence of the indole group has a large impact on the potency of tropisetron, both as an alpha 7 agonist and as an alpha(3)beta(4) antagonist. The further reduced structures of dimethyl piperidinium and 1-methylpyrrolidine also had agonist activity on alpha 7 receptors, suggesting that the minimal activating pharmacophore of these compounds, as with tetramethylammonium, may simply be the charged nitrogen, while additional structure elements impact subtype selectivity, potency, and efficacy. It has previously been reported that 5-hydroxyindole (5HI) can potentiate alpha 7 receptor responses to acetylcholine (ACh). However, the site where 5HI binds to the receptor is not known. We tested the hypothesis that the tropisetron binding site might overlap the 5HI site and thereby produce a block of 5HI potentiation. Our results indicate that the indole portion of tropisetron is not likely to be binding to the same site where 5HI binds to potentiate alpha 7 receptor responses since 5HI can greatly potentiate responses of tropisetron, tropinone, and other partial agonists such as 40H-GTS-21. (c) 2004 Elsevier Ireland Ltd. All rights reserved.