Pridopidine: Overview of Pharmacology and Rationale for its Use in Huntington’s Disease

Abstract

Despite advances in understanding the pathophysiology of Huntington’s disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo effect.This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects, and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo, pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine, and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD.

Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases

“…The mechanism of action was initially proposed to involve low-affinity/fast-off negative modulation of dopamine D2 receptors with a slight binding preference for the agonist binding site when the receptor is in the active, catalytic, high-affinity state (Nilsson et al, 2004; Rung et al, 2008; Waters et al, 2014), but the affinity of pridopidine for D2 receptors of dopamine is relatively low being in the micromolar range (Dyhring et al, 2010). Unlike classical D2 receptor antagonists, pridopidine does not induce hypoactivity or catalepsy (Waters et al, 2018). Pridopidine also has micomolar affinity for several additional GPCRs including adrenergic alpha 2A/C receptors, serotonergic 5HT1A and 5HT2A receptors, and histamine H3 receptors (Gronier et al, 2013) and these interactions may influence levels of extracellular monoamines and glutamatergic neurotransmission (Waters et al, 2014).…”

Therapeutic Advances for Huntington’s Disease

“…Pridopidine is a modulator of the dopamine 2 receptor [130] and activates the sigma-1 receptor [131]. In the most recent trials of pridopidine, no improvement in motor symptoms (unified Huntington's Disease rating scale -total motor score (UHDRS-TMS)) was observed with placebo [132][133][134].…”

Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor

“…As LTP causes mushroom spine formation (Bourne and Harris, 2007) and blockade of LTP by Aβ42 application leads to a reduction in spine abundance (Rammes et al, 2018), the reversal of LTP deficits and mushroom spine loss by pridopidine may involve the same mechanism. Indeed, both LTP and mushroom spine formation are largely induced by NMDA receptor currents (Matsuzaki et al, 2004;Noguchi et al, 2005) and S1R activity is thought to promote NMDA receptor function (Martina et al, 2007;Waters et al, 2018), possibly through increased trafficking to the plasma membrane (Pabba et al, 2014). Thus, facilatation of NMDA receptor activity may have contributed to the rescue of LTP and mushroom spine loss caused by Aβ42 oligomer toxicity.Pre-incubation of CA1 pyramidal neurons with 30 nM pridopidine had no effect on basal LTP ( Fig.…”