title: The dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162 display dopamine D(2) receptor antagonism and fast receptor dissociation properties.
abstract: 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 D(2) 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 D(2) receptor functional and binding assays. Neither ACR16, (-)-OSU6162, nor NS30678 displayed detectable dopamine D(2) receptor-mediated intrinsic activity, whereas they concentration-dependently antagonized dopamine-induced responses with IC(50) values of 12.9microM, 5.8microM, and 7.0nM, respectively. In contrast to the high-affinity typical antipsychotics haloperidol and raclopride, the dopaminergic stabilizers ACR16 and (-)-OSU6162 both displayed fast dopamine D(2) 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 D(2) receptor antagonism, possibly allowing for temporally variable and activity-dependent dopamine D(2) receptor occupancy that may partly account for their unique stabilization of dopamine dependent behaviors in vivo.
authors.affiliation: Drug Discovery, NeuroSearch A/S, Ballerup, Denmark. tdy@neurosearch.dk
authors.forename: Tino
authors.initials: T
authors.lastname: Dyhring
authors.forename: Elsebet Ø
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: Clas
authors.initials: C
authors.lastname: Sonesson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pettersson
authors.forename: Jonas
authors.initials: J
authors.lastname: Karlsson
authors.forename: Peder
authors.initials: P
authors.lastname: Svensson
authors.forename: Palle
authors.initials: P
authors.lastname: Christophersen
authors.forename: Nicholas
authors.initials: N
authors.lastname: Waters
mesh_terms: D002460:Cell Line; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D007700:Kinetics; D008024:Ligands; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D010880:Piperidines; D017448:Receptors, Dopamine D2; C109513:OSU 6162; C483720:pridopidine