Pridopidine | Sigma-1 ligand Neuroprotectant/Neurorestorative

Pridopidine (346688-38-8) is being studied as a potential treatment for Huntington’s disease, Parkinson’s disease, and schizophrenia based on its locomotor stabilizing and antipsychotic-like effects.^1,2 It was, unusually, able to reverse both hypo- and hyperdopaminergia depending on local dopamine concentrations without inducing catalepsy. This was originally attributed to functional dopamine D2 antagonism with fast on/off kinetics (“dopamine stabilizer”).³ More recent studies have attributed pridopidine’s effects to its being a more potent sigma-1 ligand than a D2 ligand.^4,5 Displays neuroprotective/restorative effects^6,7 and ameliorates central features of amyotrophic lateral sclerosis pathology⁸ in a sigma-1-mediated manner

References/Citations:

1) Pettersson (2010), 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); J.Med.Chem. 53 2510
2) The dopamine stabilizers (S)-(-)-(3-methanesulfonylphenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-methanesulfonylphenyl)-1-propyl-piperidine (ACR16) show high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and low potential for motor side effects in the rat; J.Pharmacol.Exp.Ther. 318 810
3) Dyhring et al. (2010) The dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162 display dopamine D(2) receptor antagonism and fast receptor dissociation properties; Eur.J.Pharmacol. 628 19
4) Sahlholm (2015) Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses; Psychopharmacology (Berl) 232 3443
5) Sahlholm et al. (2013), The dopamine stabilizers ACR16 and (-)-OSU6162 display nanomolar affinities at the s-1 receptor; Mol.Psychiatry 18 12
6) Francardo et al. (2019), Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson’s Disease; Neurotherapeutics 16 465
7) Ryskamp, et al. (2017), The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease; Neurobiol.Dis. 97(Pt A) 46
8) Ionescu et al. (2019), Targeting the Sigma-1 Receptor via Pridopidine Ameliorates Central Features of ALS Pathology in a SOD1G93A Model; Cell Death Dis. 10 210