Pridopidine

Pridopidine (ACR16; 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; CAS 346688-38-8; molecular formula C15H23NO2S; molecular weight 281.41) is a selective sigma-1 receptor (S1R) agonist with a binding affinity (Ki) of approximately 57 nM at the human sigma-1 receptor and substantially lower affinity at the dopamine D2 receptor (Ki approximately 2950 nM), the dopamine D3 receptor (Ki approximately 1630 nM), the adrenergic alpha-2C receptor (Ki approximately 1580 nM), and the sigma-2 receptor (Ki approximately 5450 nM). The compound was synthesized at A. Carlsson Research (later NeuroSearch) as part of a structure-activity exploration of 4-phenylpiperidine dopamine D2 receptor ligands with fast dissociation kinetics and was originally classified as a “dopaminergic stabilizer” on the basis of its state-dependent modulation of dopaminergic tone in behavioral models. Subsequent binding, functional, and positron emission tomography studies established that the principal pharmacological target at clinically relevant concentrations is the sigma-1 receptor, an endoplasmic reticulum chaperone protein located at the mitochondria-associated membrane that regulates calcium homeostasis, mitochondrial function, brain-derived neurotrophic factor (BDNF) trafficking and secretion, endoplasmic reticulum stress responses, autophagy, and synaptic plasticity. Pridopidine has demonstrated neuroprotective and neurorestorative activity in preclinical models of Huntington disease (YAC128 transgenic mice, R6/2 mice), amyotrophic lateral sclerosis (SOD1G93A mice), Parkinson disease (6-OHDA lesioned mice), and glaucoma (optic nerve crush and microbead occlusion models), with effects dependent on sigma-1 receptor activation and abolished in sigma-1 receptor knockout animals.

Clinical development has focused primarily on Huntington disease. Four randomized controlled trials (Lundin 2010, MermaiHD, HART, PRIDE-HD) evaluated pridopidine at doses of 20 to 112.5 mg per day in a combined population of over 1,100 patients. The Phase 3 MermaiHD trial (437 patients, 26 weeks) did not meet its primary motor endpoint (modified Motor Score) but demonstrated nominally significant improvement on the total Unified Huntington’s Disease Rating Scale (UHDRS) Total Motor Score. The Phase 2 PRIDE-HD trial (408 patients, 52 weeks) reported that pridopidine 45 mg twice daily was associated with maintenance of Total Functional Capacity (TFC) compared to placebo at 52 weeks, a finding extended to five years in the Open-HART open-label extension. The Phase 3 PROOF-HD trial (499 patients, 65 weeks) did not meet its primary endpoint (TFC change) in the overall population but demonstrated statistically significant benefit on TFC, composite UHDRS score, and multiple secondary endpoints in the pre-specified subgroup of participants not receiving antidopaminergic medications. A European Marketing Authorisation Application was submitted in 2024 for the treatment of adults with Huntington disease; the Committee for Medicinal Products for Human Use recommended refusal in July 2025, and Prilenia Therapeutics has announced plans for a confirmatory global Phase 3 study.

In amyotrophic lateral sclerosis, pridopidine was evaluated in the Phase 2 HEALEY ALS Platform Trial (121 participants, 24 weeks). The primary endpoint (ALSFRS-R total score change) was not met in the full analysis set, but subgroup analyses in patients with early and rapidly progressive disease demonstrated a 32 percent slowing of ALSFRS-R decline, a 62 percent slowing of respiratory decline, and a prolongation of median survival from approximately 300 to 600 days. The United States Food and Drug Administration cleared a pivotal Phase 3 trial (PREVAiLS, 500 patients) in December 2025, with recruitment planned for early 2026.

Pharmacokinetics are characterized by oral absorption, hepatic CYP2D6-mediated N-depropylation, and a single-dose elimination half-life of approximately 6 hours in extensive CYP2D6 metabolizers and 15 hours in poor metabolizers. Pridopidine is a metabolism-dependent inhibitor of CYP2D6, producing auto-inhibition that extends the effective half-life to 10 to 14 hours regardless of CYP2D6 genotype on repeated dosing, an unusual pharmacokinetic property that reduces inter-individual variability at steady state and eliminates the requirement for CYP2D6 genotype-based dose adjustment. The compound is well tolerated at doses up to 112.5 mg per day; the most common adverse events are insomnia, diarrhea, nausea, and dizziness, with no clinically significant differences from placebo in serious adverse event rates across pooled trial data. QTc prolongation at the 45 mg twice daily dose is not considered clinically relevant.

This monograph reviews the chemistry and synthesis of pridopidine; the sigma-1 receptor mechanism in molecular and cellular detail; the comprehensive pharmacokinetic record including CYP2D6 auto-inhibition; the preclinical neuroprotective evidence across multiple disease models; the clinical evidence base across Huntington disease, amyotrophic lateral sclerosis, and exploratory indications; sourcing and quality verification considerations; reconstitution and handling; stack-interaction implications; adverse-event signal; and a structured comparative assessment of five sigma-1 receptor candidates against pridopidine on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation). The compound is not approved by any regulatory authority as of the monograph revision date. It is available as a research-grade preparation from multiple chemical suppliers; investigators should obtain analytical confirmation of identity and purity on every lot.