zacopride hydrochloride is a highly potent 5-ht3 receptor antagonist and 5-ht4 agonist (ki values are 0.38 and 373 nm, respectively) [1].5-ht3 and 5-ht4 receptors belong to 5-ht receptors which are a group of g protein-coupled receptor and ligand-gated ion channels located in the central and peripheral systems. 5-ht receptors play important roles in mediating both excitatory and inhibitory neurotransmission [1].on perifused human adrenocortical slices, administration of 20-min pulses of zacopride (10-11 ~ 10-6 mol/l) induced aldosterone secretion in a dose-dependent manner. the minimal effective dose was 10-10 mol/l, and half-maximal stimulation was achieved at a dose of 7 × 10-8 mol/l [2].in 28 healthy volunteers pretreated with dexamethasone, and then a single oral dose of placebo, 10 μg zacopride, or 400 μg zacopride, plasma aldosterone levels increased significantly within 90 min after the administration of 400 μg zacopride, remained elevated for 60 min, and gradually recovered to the baseline within 180 min. however, the administration of 10 μg zacopride or placebo did not modify the aldosterone concentration. no significant changes were observed in renin, adrenocorticotropic hormone, or cortisol levels [2].[1]. nagakura y, akuzawa s, miyata k, et al. pharmacological properties of a novel gastrointestinal prokinetic benzamide selective for human 5-ht4 receptor versus human 5-ht3 receptor. pharmacological research, 1999, 39(5): 375-382.[2]. lefebvre h, contesse v, delarue c, et al. effect of the serotonin-4 receptor agonist zacopride on aldosterone secretion from the human adrenal cortex: in vivo and in vitro studies. the journal of clinical endocrinology and metabolism, 1993, 77(6): 1662-1666.
Zacopride is a sub-nanomolar antagonist of the serotonin 5-HT3 receptor that also displays agonist-like activity against 5-HT4 receptors. It is a potent anxiolytic in animal models, and also has strong antiemetic effects, and also increases aldosterone levels via activation of 5-HT4 receptor in the adrenal glands.
