Allosteric modulation of 5-HT3 serotonin receptors

[3H]Granisetron binding to 5-HT3 type serotonin receptors was examined in homogenates of rat forebrain and NG 108-15 cells. We have applied an allosteric model to 5-HT3 receptor binding for the first time. Slope factors of displacement improved the modelling. Serotonin displaced [3H]granisetron binding with micromolar potency in forebrain and with nanomolar potency in NG 108-15 cells. Racemic and (+)verapamil, ifenprodil and GYKI-46903 were used as representative allosteric inhibitors of 5-HT3 receptors. They displaced [3H]granisetron binding with great negative cooperativity (α > 10) and exerted great negative cooperativity with serotonin binding (β > 10). Great negative cooperativity of these agents with serotonin and [3H]granisetron binding cannot be distinguished from dual competitive displacement. Trichloroethanol (data from literature) had no cooperativity with [3H]granisetron binding (α ~ 1) and exhibit positive cooperativity with serotonin (β < 1) in displacement. The allosteric model can lead to a more quantitative method in vitro to develop allosteric agents for 5-HT3 receptors.