Synthesis and evaluation of a set of 4-phenylpiperidines and 4-phenylpiperazines as D2 receptor ligands and the discovery of the dopaminergic stabilizer 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (huntexil, pridopidine, ACR16).

doi:10.1021/jm901689v

Paper

Synthesis and evaluation of a set of 4-phenylpiperidines and 4-phenylpiperazines as D2 receptor ligands and the discovery of the dopaminergic stabilizer 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (huntexil, pridopidine, ACR16).

Published Feb 15, 2010 · F. Pettersson, H. Pontén, N. Waters

Journal of medicinal chemistry

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54

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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.

In Vitro Study

Study Snapshot

Pridopidine, a novel dopamine type 2 receptor antagonist with fast-off kinetic properties, exhibits unique "dopaminergic stabilizer" characteristics, allowing receptors to rapidly regain responsiveness and varying its effects based on local dopamine concentration fluctuations.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Synthesis and evaluation of a set of 4-phenylpiperidines and 4-phenylpiperazines as D2 receptor ligands and the discovery of the dopaminergic stabilizer 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (huntexil, pridopidine, ACR16).

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References

Citations

Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight

This study identified nine D2R/D3R-selective ligands, which could benefit drug development for D2R/D3R-associated pathologies like Parkinson's Disease.

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Pridopidine (ACR16) shows potential as a treatment for Alzheimer's disease by promoting synaptogenesis, reducing memory deficits, and exhibiting neuroprotective properties against oxidative stress and excitotoxicity.

ART─An Amino Radical Transfer Strategy for C(sp2)-C(sp3) Coupling Reactions, Enabled by Dual Photo/Nickel Catalysis.

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Prescribed drugs containing nitrogen heterocycles: an overview

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IRL790, a novel psychomotor stabilizer, rapidly improves synaptic markers and neurotransmission in Parkinson's disease patients by rapidly eliciting changes in protein levels and phosphorylation states.

Treatment Paradigms in Huntington’s Disease

Huntington's disease treatment relies on drugs developed for other central nervous system disorders, with potential future treatments based on drug candidates in clinical development.