In Vivo Systems Response Profiling and Multivariate Classification of CNS Active Compounds: A Structured Tool for CNS Drug Discovery

Abstract

This paper describes the application of in vivo systems response profiling in CNS drug discovery by a process referred to as the Integrative Screening Process. The biological response profile, treated as an array, is used as major outcome for selection of candidate drugs. Dose-response data, including ex vivo brain monoaminergic biomarkers and behavioral descriptors, are systematically collected and analyzed by principal component analysis (PCA) and partial least-squares (PLS) regression, yielding multivariate characterization across compounds. The approach is exemplified by assessing a new class of CNS active compounds, the dopidines, compared to other monoamine modulating compounds including antipsychotics, antidepressants, and procognitive agents. Dopidines display a distinct phenotypic profile which has prompted extensive further preclinical and clinical investigations. In summary, in vivo profiles of CNS compounds are mapped, based on dose response studies in the rat. Applying a systematic and standardized work-flow, a database of in vivo systems response profiles is compiled, enabling comparisons and classification. This creates a framework for translational mapping, a crucial component in CNS drug discovery.

(3S)‐3‐(2,3‐difluorophenyl)‐3‐methoxypyrrolidine (IRL752) —a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent

“…Postmortem concentrations of several monoaminergic indices (DA, NA, 5-HT, DOPA, HVA, 3-MT, 5-HIAA) were determined in striatal, limbic, and cortical tissue; collected; and dissected 64 minutes after administration of IRL752 (3.7-100 mmol/kg, s.c.) to normal rats, immediately after a 60-minute motor activity recording session (see below). Tissue sample preparation and neurochemical content analysis of monoamines and their metabolites (standard high-performance liquid chromatography with electrical detection) were carried out as described elsewhere (Waters et al, 2017).…”

“…Behavior: In Habituated and Nonhabituated, Nonpretreated Rats and in Monoamine-Depleted, Hyperdopaminergic, or Hypoglutamatergic States. The behavior of rats was recorded in sound-and light-attenuating motor activity-monitoring chambers equipped with infrared movement detectors (two rows, each consisting of 16 sensors placed 2.5 cm apart and placed in a 90°angle along the front and side of the floor of the cage; Digiscan Activity Monitor RZYCCM-16 TAO; Omnitech Electronics), thus allowing for high-resolution assessment of motor patterns across a 40 Â 40 cm-sized arena using several different sampling frequencies (0.25-25 Hz) in parallel (for further details, see Waters et al, 2017). Only data from the 25-Hz sampling channel (distance traveled) are shown in the Results.…”

“…(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752; Fig. 1) is a novel compound discovered and developed in an in vivo systems pharmacology (see Waters et al, 2017) program aiming to generate novel agents with a preferential enhancing effect on cortical versus subcortical catecholamine [dopamine (DA) and noradrenaline (NA)] output. The current report describes the actions of this agent on regional neuronal transmission in vivo, behavior, cognition, and synaptic activity-related gene expression in the rat.…”

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

“…The theory is that systematic in vivo profiling of CNS compounds, using a comprehensive range of neurochemical, gene expression and behavioral biomarkers collected in both healthy and diseased states, would give a reliable handle on preclinical properties and allow for predictions of clinical features of the novel compounds tested in the system. Data on a wide variety of known therapeutic agents including antipsychotics, antidepressants, anxiolytics and psychostimulants, as well as experimental reference compounds, are collected, and then used to define a multidimensional compound “map” serving as a guide towards the sought after in vivo profile [ 69 ]. This methodology was developed to enable a rational and predictive drug discovery process in a field where target-based discovery approaches have hitherto shown to be largely unsatisfactory in terms of determining clinically promising molecules and molecular action mechanisms [ 70 ].…”

“…The initial in vivo pharmacological assessment of pridopidine was performed by acute dose response studies in intact rats, collecting behavioral data and ex vivo monoaminergic neurochemical indices according to a systematic, standardized model, followed by multivariate analysis of the response profile, including comparisons to a wide range of CNS compounds and a tentative therapeutic classification [ 69, 73 ]. This “screening” suggested that three major criteria were met; i.e., no behavioral inhibition, subtle behavioral activation in the hypoactive phase, and significant effects on dopaminergic indices reflecting dopamine D2 receptor modulation.…”