Preclinical Evaluation of the Effects of Trazpiroben (TAK-906), a Novel, Potent Dopamine D 2 /D 3 Receptor Antagonist for the Management of Gastroparesis

Current therapies for gastroparesis metoclopramide and domperidone carry risks of extrapyramidal symptoms and life-threatening cardiac arrhythmias. Trazpiroben, a novel, potent dopamine D /D receptor antagonist, has low brain permeation and very low affinity for human ether-à-go-go-related gene (hERG) channel inhibition, potentially improving on safety profiles of existing therapies. Trazpiroben demonstrated the following receptor affinities: high for D and D , moderate for D , and minimal for D and D It demonstrated moderate affinity for adrenergic 1B ( ) and 5-hydroxytryptamine (5HT) 2A receptors and low potential for off-target adverse events (AEs). Trazpiroben potently inhibited dopamine-activated D receptor activation of cognate G-proteins in human embryonic kidney 293 cell membranes and was a neutral D receptor antagonist. In vivo, trazpiroben dose-dependently increased prolactin release in orally dosed rat (0.1-1 mg/kg). Additionally, multiple oral doses in the rat (100 mg/kg) and dog (50 mg/kg) for 3 days produced robust plasma exposures and prolactin increases in both species. Trazpiroben inhibited retching/vomiting in the dog with apomorphine-induced emesis with a potency (0.1-1 mg/kg) like that of trazpiroben-mediated prolactin increases in rat. Oral trazpiroben (1, 10, and 30 mg/kg) did not affect rat rotarod performance, suggesting low brain penetration. Trazpiroben concentrations were low in cerebrospinal fluid versus plasma after multiple oral doses for 4 days in rat and dog. Trazpiroben weakly inhibited the hERG channel current (concentration causing half-maximal inhibition of control-specific binding of 15.6 µM), indicating little potential for disrupting cardiac rhythm. Overall, trazpiroben is a potent D /D receptor antagonist designed to avoid the serious potential AEs associated with current gastroparesis therapies. SIGNIFICANCE STATEMENT: Trazpiroben is a novel, potent dopamine D /D selective receptor antagonist designed to avoid adverse effects associated with the current pharmacological therapies metoclopramide and domperidone. Preclinical studies have demonstrated low brain penetration and weak affinity for the hERG channel, indicating that trazpiroben is not expected to be associated with central nervous system or cardiovascular safety issues. With these pharmacological properties, trazpiroben may represent a viable new treatment option for gastroparesis because of a potentially improved safety profile relative to existing therapie