4-(2-chlorophenyl)butan-2-amine and Parkinson-Disease

Impairment in various aspects of cognition is recognized as an important non-motor symptom of Parkinson's disease (PD). Mild cognitive impairment in PD (PD-MCI) is common in non-demented PD patients and is often associated with severity of motor symptoms, disease duration and increasing age. Further, PD-MCI can have a significant negative effect on performance of daily life activities and may be a harbinger of development of PD dementia. Thus, there is significant interest in developing therapeutic strategies to ameliorate cognitive deficits in PD and improve cognitive functioning of PD patients. However, due to significant questions that remain regarding the pathophysiology of cognitive dysfunction in PD, remediation of cognitive dysfunction in PD has proven difficult. In this paper, we will focus on PD-MCI and will review some of the current therapeutic approaches being taken to try to improve cognitive functioning in patients with PD-MCI.

Topics: Butylamines; Cholinergic Agents; Clinical Trials as Topic; Cognitive Dysfunction; Dopamine Agents; Humans; Neuropsychological Tests; Parkinson Disease; Serotonin Agents; Treatment Outcome

Mild cognitive impairment is present in a number of neurodegenerative disorders including Parkinson's disease (PD). Mild cognitive impairment in PD (PD-MCI) often manifests as deficits in executive functioning, attention, and spatial and working memory. Clinical studies have suggested that the development of mild cognitive impairment may be an early symptom of PD and may even precede the onset of motor impairment by several years. Dysfunction in several neurotransmitter systems, including dopamine (DA), norepinephrine (NE), may be involved in PD-MCI, making it difficult to treat pharmacologically. In addition, many agents used to treat motor impairment in PD may exacerbate cognitive impairment. Thus, there is a significant unmet need to develop therapeutics that can treat both motor and cognitive impairments in PD. We have recently developed SK609, a selective, G-protein biased signaling agonist of dopamine D3 receptors. SK609 was successfully used to treat motor impairment and reduce levodopa-induced dyskinesia in a rodent model of PD. Further characterization of SK609 suggested that it is a selective norepinephrine transporter (NET) inhibitor with the ability to increase both DA and NE levels in the prefrontal cortex. Pharmacokinetic analysis of SK609 under systemic administration demonstrated 98% oral bioavailability and high brain distribution in striatum, hippocampus and prefrontal cortex. To evaluate the effects of SK609 on cognitive deficits of potential relevance to PD-MCI, we used unilateral 6-hydroxydopamine (6-OHDA) lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus macaques, with deficits in performance in a sustained attention and an object retrieval task, respectively. SK609 dose dependently improved the performance of 6-OHDA-lesioned rats, with peak performance achieved using a 4 mg/kg dose. This improvement was predominantly due to a significant reduction in the number of misses and false alarm errors, contributing to an increase in sustained attention. In MPTP-lesioned monkeys, this same dose also improved performance in an object retrieval task, significantly reducing cognitive errors (barrier reaches) and motor errors (fine motor dexterity problems). These data demonstrate that SK609 with its unique pharmacological effects on modulating both DA and NE can ameliorate cognitive impairment in PD models and may provide a therapeutic option to treat both motor and cognitive impairment in PD patients.

Topics: Animals; Attention; Brain; Butylamines; Cognitive Dysfunction; Dopamine Agonists; Hydroxydopamines; Macaca fascicularis; Male; MPTP Poisoning; Norepinephrine Plasma Membrane Transport Proteins; Parkinson Disease; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D3

Synthetic dopaminergic agents have found utility in treating neurological and neuropsychiatric disorders since the beginning of 19th century. The discovery of Levodopa (l-dopa) to effectively treat motor symptoms of Parkinson's disease (PD) revolutionized the therapy and remains a gold standard for treating PD. However, l-dopa therapy has been implicated in worsening of the non-motor symptoms including cognition and long-term therapy leads to plasticity and development of abnormal involuntary movements (AIMs) that are collectively called l-dopa induced dyskinesias (LID). Studies in rodents and non-human primates with PD have supported a role for dopamine D3 receptors in the etiology of both the motor symptoms and LID. We have recently developed SK609, a selective dopamine D3 receptor agonist with atypical signaling properties. In this study, we further characterized this novel small molecule using the unilateral lesioned rodent model of PD. In the forepaw stepping test paradigm, SK609 significantly improved the performance of the impaired paw and also normalized the bilateral asymmetry associated with the hemiparkinson rat. In addition, a chronic treatment of SK609 did not induce any AIMs and when used adjuvantly with l-dopa significantly reduced AIMs induced by l-dopa. Further, an optimal dose combination of SK609 with l-dopa was determined by dose dependent titrations of both SK609 and l-dopa that produced minimal AIMs and maximized the effect on improving motor symptoms. Results from this study suggest that SK609 is a novel dopaminergic agent that has the therapeutic potential to treat PD and LID. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.

Topics: Animals; Antiparkinson Agents; Butylamines; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Levodopa; Male; Motor Activity; Parkinson Disease; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D3