Synthesis and Evaluation of a Set of 4-Phenylpiperidines and 4-Phenylpiperazines as D₂Receptor Ligands and the Discovery of the Dopaminergic Stabilizer 4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine (Huntexil, Pridopidine, ACR16)

Abstract

Modification of the partial dopamine type 2 receptor (D(2)) agonist 3-(1-benzylpiperidin-4-yl)phenol (9a) generated a series of novel functional D(2) antagonists with fast-off kinetic properties. A representative of this series, pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; ACR16, 12b), bound competitively with low affinity to D(2) in vitro, without displaying properties essential for interaction with D(2) in the inactive state, thereby allowing receptors to rapidly regain responsiveness. In vivo, neurochemical effects of 12b were similar to those of D(2) antagonists, and in a model of locomotor hyperactivity, 12b dose-dependently reduced activity. In contrast to classic D(2) antagonists, 12b increased spontaneous locomotor activity in partly habituated animals. The "agonist-like" kinetic profile of 12b, combined with its lack of intrinsic activity, induces a functional state-dependent D(2) antagonism that can vary with local, real-time dopamine concentration fluctuations around distinct receptor populations. These properties may contribute to its unique "dopaminergic stabilizer" characteristics, differentiating 12b from D(2) antagonists and partial D(2) agonists.

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

“…This is an important characteristic because DA has a higher affinity for D1-like receptors than for D2-like receptors [355]. Evidence suggests, however, that D 2 receptors located pre-synaptically to modulate the release of transmitters are in a high-affinity state (D 2 high ) and display slower K off , while postsynaptic receptors are equally distributed between high and low affinity states [356]. Thus, it may be possible to use the affinity state of DA receptors to develop more effective treatments.…”

“…It has a K i  = 7521 nM for D 2 receptors high but a K i  = 17550 nM for D 2 receptors low . In addition, pridopidine rapidly dissociates from the receptor (K off ) and binds primarily to activated D 2 receptors [356]. …”

Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism

“…Interestingly, quetiapine showed similar behavior in those experiments. Table 3 Fast response: max effect<1 min Transient (successive, very short intervals) Variable see Table 3 High See Attention is also focused on the likelihood of receptor reserve (i.e., cellular amplification of the D 2 receptor-generated signal) and popularity (i.e., prevalence) of the assay in question in the D 2 receptor domain a Potential relevance Alongside, these authors (Dyhring et al 2010;Pettersson et al 2010) also compared the dissociation rates of clozapine, quetiapine, and selected "dopamine stabilizers" in an alternative experimental setting that is reminiscent to the earlier evoked multi-step/intermediate "washout" radioligand binding procedures depicted in Fig. 2.…”

Pridopidine reverses phencyclidine-induced memory impairment

“…Pridopidine (formerly ACR16), was originally developed as a fast-dissociating, micromolar affinity dopamine D 2 receptor (D 2 R) antagonist (Pettersson et al, 2010), showing antipsychotic-like activity in rodents with low liability to induce catalepsy (Nilsson et al, 2004;Natesan et al, 2006;Ponten et al, 2010) and pro-social effects in MK-801-treated rats (Rung et al, 2005). Later, pridopidine was found to possess nanomolar sigma-1 receptor (sigma-1R) affinity, displaying a corresponding preference for sigma-1R over D 2 R in vivo (Sahlholm et al, 2013(Sahlholm et al, , 2015.…”