Abstract
Here we describe for the first time the distinctive pharmacological profile for (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 µmol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypoactivity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to ∼250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to ∼250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptamine 7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT: This report describes the distinctive preclinical profile of (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.
Highlights
Parkinson disease (PD) is primarily associated with its well-known motor manifestations, such as slowness and poverty of movements, resting tremor, muscular rigidity, and postural dysfunction
IRL752 had no significant effect on acute hyperdopaminergic or hypoglutamatergic motor responses but reversed deficits resulting from hypomonoaminergic function
The behavioral characteristics of IRL752 are consistent with a capacity to normalize impaired catecholamine function while avoiding overactivation of central nervous system (CNS) systems and circuits involved
Summary
Parkinson disease (PD) is primarily associated with its well-known motor manifestations, such as slowness and poverty of movements, resting tremor, muscular rigidity, and postural dysfunction. It is becoming increasingly recognized that several nonmotor symptoms are prominently represented in PD, some of which may temporally precede the motor impairments (Chaudhuri et al, 2015; Sauerbier et al, 2016). Among the nonmotor symptoms in PD, cognitive deficits are highly prevalent (e.g., Willis et al, 2012). Cognitive symptoms may present early (Aarsland et al, 2009), with their prevalence rising dramatically over the IRL752—a Cortical-Preferring Cognition-Promoting Agent. Ki data plotted (filled circles) in a radar-type diagram with an excentric scale from 0 to 30 mM.
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