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

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 mmol/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 cognitionrelated immediate early genes (IEGs), however, increased by 1.5fold 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 transmissionpromoting 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 a2(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.

Treatment of Apathy in Parkinson’s Disease and Implications for Underlying Pathophysiology

“…Pirepemat is a novel small-molecule compound classified as a cortical enhancer, demonstrating regioselective potentiation of cortical norepinephrine, dopamine, and acetylcholine [70]. A phase 2b RCT demonstrated the safety and tolerability of pirepemat for treating PD, with a significant reduction in apathy severity scores as measured using the NPI at 4 weeks [27].…”

First‐in‐Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Pirepemat, a Cortical Enhancer, in Healthy Volunteers

“…12 The pharmacologic profile of pirepemat has been found to be consistent with a cortically regioselective facilitatory impact on cortical neurotransmission, as well as cognitive impairmentreversing features. 13 In vitro neurotarget affinity and functional data suggest 5-hydroxytryptamine 7 receptor and α2C-adrenoceptor antagonism are key contributors to the in vivo efficacy profile of pirepemat. 13 In vivo pharmacokinetics (PK) of pirepemat in rats and dogs is characterized by complete and rapid absorption, wide tissue distribution including the central nervous system, and log-linear elimination.…”

“…13 In vitro neurotarget affinity and functional data suggest 5-hydroxytryptamine 7 receptor and α2C-adrenoceptor antagonism are key contributors to the in vivo efficacy profile of pirepemat. 13 In vivo pharmacokinetics (PK) of pirepemat in rats and dogs is characterized by complete and rapid absorption, wide tissue distribution including the central nervous system, and log-linear elimination. Pirepemat is eliminated through a combination of renal excretion of the parent compound and metabolic transformation involving cytochrome P450 (CYP) oxidations and formation of glucuronide conjugates.…”