TY - JOUR T1 - Preclinical Evaluation of the<em> </em>Effects of Trazpiroben (TAK-906), a Novel, Potent Dopamine D<sub>2</sub>/D<sub>3</sub> Receptor Antagonist for the Management of Gastroparesis JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.121.000698 SP - JPET-AR-2021-000698 AU - Roger L Whiting AU - Agnes Choppin AU - Gary Luehr AU - Jeffrey R. Jasper Y1 - 2021/01/01 UR - http://jpet.aspetjournals.org/content/early/2021/07/12/jpet.121.000698.abstract N2 - Current therapies for gastroparesis, metoclopramide and domperidone, carry risks of extrapyramidal symptoms and life-threatening cardiac arrhythmias. Trazpiroben, a novel, potent dopamine D2/D3 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 D2 and D3, moderate for D4 and minimal for D1 and D5. It demonstrated moderate affinity for adrenergic alpha 1B (α1B) and 5-hydroxytryptamine 2A (5HT2A) receptors and low potential for off-target adverse events (AEs). Trazpiroben potently inhibited dopamine-activated D2L receptor activation of cognate G-proteins in human embryonic kidney 293 cell membranes and was a neutral D2L receptor antagonist. In vivo, trazpiroben dose-dependently increased prolactin release in orally dosed rat (0.1-1mg/kg). Additionally, multiple oral doses in the rat (100mg/kg) and dog (50mg/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 (0.1-1mg/kg) like that of trazpiroben-mediated prolactin increases in rat. Oral trazpiroben (1, 10, and 30mg/kg) did not affect rat rotarod performance, suggesting low brain penetration. Trazpiroben concentrations were low in cerebrospinal fluid versus plasma following 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 15.6µM), indicating little potential for disrupting cardiac rhythm. Overall, trazpiroben is a potent D2/D3 receptor antagonist designed to avoid serious potential AEs associated with current gastroparesis therapies. Significance Statement Trazpiroben is a novel, potent dopamine D2/D3 selective receptor antagonist designed to avoid adverse effects associated with the current pharmacological therapies, metoclopramide and domperidone. Pre-clinical 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 due to a potentially improved safety profile relative to existing therapies. ER -