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

The α7 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 α7. α4β2, or α3β4 nAChR or rat 5HT3A receptors. The simple compounds tropane and tropinone had α7-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 α3β4 nAChR but no effect on α4β2 nAChR. Some tropanes also affected the responses of 5HT3 receptors to serotonin. Tropisetron was more potent at inhibiting α3β4 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 α7 agonist and as an α3β4 antagonist. The further reduced structures of dimethyl piperidinium and 1-methylpyrrolidine also had agonist activity on α7 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 α7 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 α7 receptor responses since 5HI can greatly potentiate responses of tropisetron, tropinone, and other partial agonists such as 4OH-GTS-21.