The dopaminergic stabilizers pridopidine (ACR16) and (−)-OSU6162 display dopamine D2 receptor antagonism and fast receptor dissociation properties

A new pharmacological class of CNS ligands with the unique ability to stimulate or suppress motor and behavioral symptoms depending on the prevailing dopaminergic tone has been suggested as “dopaminergic stabilizers”. The molecular mode-of-action of dopaminergic stabilizers is not yet fully understood, but they are assumed to act via normalization of dopaminergic signaling, through interactions with the dopamine D2 receptor. Here we have evaluated the dopaminergic stabilizers pridopidine (ACR16) and (−)-OSU6162, as well as the new compound N-{[(2S)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl}ethanamine (NS30678) in a series of cellular in vitro dopamine D2 receptor functional and binding assays. Neither ACR16, (−)-OSU6162, nor NS30678 displayed detectable dopamine D2 receptor-mediated intrinsic activity, whereas they concentration-dependently antagonized dopamine-induced responses with IC50 values of 12.9 μM, 5.8 μM, and 7.0 nM, respectively. In contrast to the high-affinity typical antipsychotics haloperidol and raclopride, the dopaminergic stabilizers ACR16 and (−)-OSU6162 both displayed fast dopamine D2 receptor dissociation properties, a feature that has previously been suggested as a contributing factor to antipsychotic atypicality and attributed mainly to low receptor affinity. However, the finding that NS30678, which is equipotent to haloperidol and raclopride, also displays fast receptor dissociation, suggests that the agonist-like structural motif of the dopaminergic stabilizers tested is a critical dissociation rate determinant. The results demonstrate that dopaminergic stabilizers exhibit fast competitive dopamine D2 receptor antagonism, possibly allowing for temporally variable and activity-dependent dopamine D2 receptor occupancy that may partly account for their unique stabilization of dopamine dependent behaviors in vivo.