The acute EPS of haloperidol may be unrelated to its metabolic transformation to BCPP+

We have previously proposed that haloperidolʹs debilitating extrapyramidal symptoms (EPS) may be associated with its quaternary BCPP+ (an MPP+ like species) metabolite formed in vivo. However, recent work on D2 knock out mice suggests that haloperidolʹs EPS may be related to its potent D2 binding (Ki=0.9 nM). In this study, we explore this question by synthesizing and testing an analogue (DS-27) that binds to D2 receptors with higher affinity than haloperidol, but cannot form quaternary metabolites. This study suggests that D2 affinity may be the primary underlying mechanism for acute catalepsy induction by haloperidol.