Antipsychotic Benzamides Amisulpride and LB-102 Display Polypharmacy as Racemates, S Enantiomers Engage Receptors D2 and D3, while R Enantiomers Engage 5-HT7

Vincent Grattan; Andrew R Vaino; Zachary Prensky; Mark S Hixon

doi:10.1021/acsomega.9b02144

Antipsychotic Benzamides Amisulpride and LB-102 Display Polypharmacy as Racemates, S Enantiomers Engage Receptors D₂ and D₃, while R Enantiomers Engage 5-HT₇

ACS Omega. 2019 Aug 15;4(9):14151-14154. doi: 10.1021/acsomega.9b02144. eCollection 2019 Aug 27.

Authors

Vincent Grattan¹, Andrew R Vaino¹, Zachary Prensky¹, Mark S Hixon²

Affiliations

¹ LB Pharmaceuticals Inc., 575 Madison Avenue, New York, New York 10022, United States.
² Mark S. Hixon Consulting LLC, 11273 Spitfire Road, San Diego, California 92126, United States.

Abstract

Benzamide antipsychotics such as amisulpride are dosed as racemates though efficacy is assumed to be mediated through S enantiomer binding to D₂ receptors. At prescribed doses, the benzamides likely display polypharmacy since brain exposure should be sufficient to engage the 5-HT₇ receptors, as well. Curiously, the studies herein reveal that racemic dosing is required to engage both targets since the D₂ receptor has an almost 40-fold selectivity for the S enantiomer, while the 5-HT₇ receptor has greater than 50-fold preference for the R enantiomer.