Background In vivo pharmacological systems-response profiling, which uses a comprehensive array of biomarkers, was developed previously as a way to obtain a sensitive and detailed “fingerprint” of the functional effects of central nervous system (CNS)-acting compounds. In terms of predicting the clinical properties of new agents, this method may be better than using single-endpoint in vivo models or relying heavily on in vitro pharmacology data.
Aims Using this method, we aimed to classify and benchmark the pharmacological and behavioural effects of pridopidine (Huntexil®, NeuroSearch A/S, Ballerup, Denmark) at a systems level. Pridopidine belongs to a class of agents called dopidines, which act as dopaminergic stabilisers, and is in development for treatment of motor symptoms associated with Huntington's disease. Thus, we also examined the effects of a range of other CNS-acting dopaminergic compounds.
Methods Standardized in vivo dose-response studies (in rats) were performed to collect an array of brain tissue-derived biomarkers and behavioural variables for a wide range of CNS-acting dopaminergic compounds (eg, antidepressants, antipsychotics, pro-cognitive compounds and dopidines). Data were quality checked and analysed by principal component analysis and partial least squares (PLS) regression. For PLS, discriminant variables representing the doses were used as the dependent variables, and the “biological responses” constituted the independent variable block.
Results The different compound classes formed clusters that largely reflected their clinical properties. Pharmacologically, the dopidines clustered between the antidepressants and antipsychotics. Behaviourally, the dopidines clustered separately from all comparator dopaminergic agents tested, including partial dopamine agonists and other fast-off dopamine D2 receptor antagonists.
Conclusions The dopidines, including pridopidine, form a distinct pharmacological cluster when studied by systematic multivariate mapping of their in vivo effects, and their overall profile is not shared by any other class of dopaminergic agents.
- multivariate classification