Comparative in vivo pharmacology of dopidines A novel class of compounds discovered by phenotypic screening

Abstract

Dopidines are a novel class of dopamine (DA) modulating compounds, developed to provide improved treatment of a range of neurodegenerative and psychiatric disorders that are currently managed to a large extent with antidopaminergic medications. The overall aim of the present work was to investigate the in vivo pharmacology of dopidines, as compared to other classes of monoamine modulating compounds. A further aim was to explore the long term effects of antidopaminergic medication in Huntington’s disease (HD), a neurodegenerative disorder characterized by motor, behavioural, and cognitive symptoms. Data from REGISTRY, an observational study on patients with HD, were analysed by means of principal component analysis, bivariate regression, and multiple regression, to assess the potential impact of antidopaminergic medications on motor and functional outcomes. The further studies were based on preclinical studies, performed in rats. Multivariate analysis was applied on in vivo systems response profiles - systematically collected dose response data on monoaminergic neurochemistry and behavioural activity - elicited by a range of monoamine modulating compounds, including i.a. dopidines, antipsychotics, antidepressants, and procognitive agents. These data were used to create multivariate maps providing a comprehensive overview of similarities, trends and clusters among the compounds, and their effects in vivo. Further, the effects of dopidines and a set of reference compounds, on Arc mRNA expression, a marker of synaptic activity, were investigated. Pharmacological interaction studies were performed with one of the dopidines, pridopidine, and tetrabenazine, comparing pridopidine’s effects with those of the DA D2 antagonist haloperidol. Outcome measures were locomotor activity, striatal DA indices, and Arc mRNA. In patients with HD, antidopaminergic medication was associated with more severe motor and functional impairment, and a faster progression rate. This finding could not be explained by factors such as age, disease duration, or CAG repeat length. While e.g. selection bias underlying the findings cannot be ruled out, the concern is raised that current antidopaminergic medications may be detrimental in HD. This signal warrant further investigation, in HD as well as in other neurodegenerative disorders, where such treatment is common practice. The in vivo profiling indicated that dopidines form a distinct pharmacological class, with antipsychotic and tentatively procognitive properties, but lacking psychomotor depression. The pattern of Arc gene expression distinguished the dopidines further from other DA modulating agents. The dopidines displayed effects suggesting synaptic activation in the frontal cortex, which is proposed to contribute to their characteristic psychomotor stabilizing effects, both in terms of efficacy in reducing locomotor activity in hyperactive states, but also with regards to their ability to relieve hypoactivity. Alleviation of hypoactivity was expressed also in a partially monoamine-depleted state induced by tetrabenazine. This has implications regarding potential benefits of coadministering tetrabenazine and pridopidine in patients with HD, and further suggests dopidines could be therapeutically useful in other neurodegenerative disorders. Based on these findings, and previously published data, a tentative model of the in vivo mode of action of this class of compounds at the level of major neuronal pathways disrupted in HD, is outlined.