Preclinical Pharmacology of [2-(3-Fluoro-5-Methanesulfonyl-phenoxy)Ethyl](Propyl)amine (IRL790), a Novel Dopamine Transmission Modulator for the Treatment of Motor and Psychiatric Complications in Parkinson Disease.

IRL790 ([2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine, mesdopetam) is a novel compound in development for the clinical management of motor and psychiatric disabilities in Parkinson disease. The discovery of IRL790 was made applying a systems pharmacology approach based on in vivo response profiling. The chemical design idea was to develop a new type of DA D3/D2 receptor type antagonist built on agonist rather than antagonist structural motifs. We hypothesized that such a dopamine antagonist with physicochemical properties similar to agonists would exert antidyskinetic and antipsychotic effects in states of dysregulated dopaminergic signaling while having little negative impact on physiologic dopamine transmission and, hence, minimal liability for side effects related to dopamine-dependent functions. At the level of in vivo pharmacology, IRL790 displays balancing effects on aberrant motor phenotypes, reducing l-DOPA-induced dyskinesias in the rodent 6-hydroxydopamine lesion model and reducing psychostimulant-induced locomotor hyperactivity elicited by pretreatment with either d-amphetamine or dizocilpine, without negatively impacting normal motor performance. Thus, IRL790 has the ability to normalize the behavioral phenotype in hyperdopaminergic as well as hypoglutamatergic states. Neurochemical and immediate early gene (IEG) response profiles suggest modulation of DA neurotransmission, with some features, such as increased DA metabolites and extracellular DA, shared by atypical antipsychotics and others, such as increased frontal cortex IEGs, unique to IRL790. IRL790 also increases extracellular levels of acetylcholine in the prefrontal cortex and ventral hippocampus. At the receptor level, IRL790 appears to act as a preferential DA D3 receptor antagonist. Computational docking studies support preferential affinity at D3 receptors with an agonist-like binding mode. SIGNIFICANCE STATEMENT: This paper reports preclinical pharmacology along with molecular modeling results on IRL790, a novel compound in clinical development for the treatment of motor and psychiatric complications in advanced Parkinson disease. IRL790 is active in models of perturbed dopaminergic and glutamatergic signaling, including rodent 6-hydroxydopamine l-DOPA-induced dyskinesias and psychostimulant-induced hyperactivity, in a dose range that does not impair normal behavior. This effect profile is attributed to interactions at dopamine D2/D3 receptors, with a 6- to 8-fold preference for the D3 subtype.

Glycine receptors involved in acamprosate's modulation of accumbal dopamine levels: an in vivo microdialysis study.

BACKGROUND: Glycine receptors (GlyRs) in the nucleus accumbens (nAc) and nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) have been suggested to be involved in the positive reinforcing and dopamine elevating effects of ethanol. Recent studies have also shown that ethanol high-preferring rats substantially decrease their ethanol intake when treated with a glycine transporter 1 inhibitor (ORG 25935). Acamprosate, a drug used for relapse prevention in treatment of alcohol dependence, has also been demonstrated to elevate extracellular dopamine levels in the nAc. However, the underlying mechanism of action of acamprosate is not fully understood. Here we investigated whether acamprosate interferes with a neuronal circuitry that previously has been demonstrated to be involved in the dopamine elevating effects of ethanol and taurine. METHODS: In vivo microdialysis in freely moving rats was used to assess accumbal dopamine levels before and during local (nAc) or systemic administration of acamprosate. RESULTS: Perfusion of 0.5 mM acamprosate in the nAc significantly increased dopamine levels. Pretreatment either with 10 microM strychnine in the nAc or 100 microM mecamylamine in the VTA, completely antagonized the acamprosate-induced elevation of accumbal dopamine levels. Also, systemic acamprosate administration elevated accumbal dopamine output, an effect that was abolished by local (nAc) pretreatment with 10 microM strychnine. CONCLUSIONS: These results suggest that both systemic and local application of acamprosate elevate extracellular dopamine levels in the nAc by activating accumbal GlyRs, and, secondarily, tegmental nAChRs.

The glycine reuptake inhibitor org 25935 interacts with basal and ethanol-induced dopamine release in rat nucleus accumbens.

BACKGROUND: The mesolimbic dopamine (DA) projection from the ventral tegmental area to nucleus accumbens (nAc), a central part of the reward system, is activated by ethanol (EtOH) and other drugs of abuse. We have previously demonstrated that the glycine receptor in the nAc and its amino acid agonists may be implicated in the DA activation and reinforcing properties of EtOH. We have also reported that the glycine transporter 1 inhibitor, Org 25935, produces a robust and dose-dependent decrease in EtOH consumption in Wistar rats. The present study explores the interaction between EtOH and Org 25935 with respect to DA levels in the rat nAc. METHODS: The effects of Org 25935 (6 mg/kg, i.p.) and/or EtOH (2.5 g/kg, i.p.) on accumbal DA levels were examined by means of in vivo microdialysis (coupled to HPLC-ED) in freely moving male Wistar rats. The effect of Org 25935 on accumbal glycine output was also investigated. RESULTS: Systemic Org 25935 increased DA output in a subpopulation of rats (52% in Experiment 1 and 38% in Experiment 2). In Experiment 2, EtOH produced a significant increase in DA levels in vehicles (35%) and in Org 25935 nonresponders (19%), whereas EtOH did not further increase the DA level in rats responding to Org 25935 (2%). The same dose of Org 25935 increased glycine levels by 87% in nAc. CONCLUSIONS: This study demonstrates that Org 25935, probably via increased glycine levels, (i) counteracts EtOH-induced increases of accumbal DA levels and (ii) increases basal DA levels in a subpopulation of rats. The results are in line with previous findings and it is suggested that the effects observed involve interference with accumbal GlyRs and are related to the alcohol consumption modulating effect of Org 25935.