Pridopidine

Pridopidine is being considered as a potential treatment for Huntington’s disease, Parkinson’s disease, and schizophrenia, because of its locomotor stabilizing and antipsychotic-like effects (1,2). Without leading to catalepsy, it can reverse both hypo- and hyperdopaminergia depending on local dopamine concentrations. This effect of pridopidine is granted to functional dopamine D2 antagonism with fast on/off kinetics (“dopamine stabilizer”) (3). Recent studies has suggested pridopidine is more of a potent sigma-1 ligand than a D2 ligand (4,5). Pridopidine also exhibits neuroprotective/restorative effects (6,7) and ameliorates central features of amyotrophic lateral sclerosis pathology (8) in a sigma-1-mediated manner.

References:

1) Pettersson et al., (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) Natesan et al., (2006), 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 et al., (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 -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 epub ahead of print

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