This grant builds upon the research from a prior grant: Preferential Targeting of Subpopulations of 5-HT1A Receptors: Microdialysis Study
Promising Outcomes of Original Grant:
These researchers are investigating the activity of novel drugs that potently activate serotonin 5-HT1A receptors. Targeting this receptor subtype is an attractive strategy to decrease the dyskinesia that arises in Parkinson’s disease (PD) patients from prolonged treatment with levodopa. Data gathered in the previous grant showed that a novel, exceptionally selective drug (NLX-112) completely abolished the dyskinesia-like symptoms observed in pre-clinical parkinsonian models with repeated levodopa treatment. NLX-112 also modified neurotransmitter release in the striatum, an important brain region for motor control.
Objectives for Supplemental Investigation:
This supplemental research is aimed at investigating two important questions. The first is whether the anti-dyskinetic effect of NLX-112 and its associated regulation of neurotransmitter release are maintained upon repeated administration. In pre-clinical models, subjects will be rendered dyskinetic and then treated repeatedly with NLX-112 for several weeks. They will be observed to determine whether NLX-112 maintains is capacity to eliminate dyskinesia and modulate neurotransmitter release.
The second question is whether NLX-112 is able to prevent the development of dyskinesia and its associated neurochemical changes. For this experiment, test subjects will be treated for several weeks with levodopa and concurrent NLX-112 (control subjects will receive only levodopa). Subjects will be observed to determine whether NLX-112 exerts a protective effect against the development of dyskinesia and changes in neurotransmitter release.
Importance of This Research for the Development of a New PD Therapy:
Attempts to target 5-HT1A receptors with older drugs have not been satisfactory, notably due to their poor selectivity and weak partial agonism. In contrast, NLX-112 exhibits very high selectivity, “full agonism” (activation) at 5-HT1A receptors and promising activity in pre-clinical models of levodopa-induced dyskinesia. The present studies are anticipated to provide evidence supporting the capacity of NLX-112 to control dyskinesia under extended treatment conditions and, potentially, to prevent the development of dyskinesia altogether. Such results would strengthen the rationale for pursuing a clinical development program for NLX-112.
Final Outcome
The project showed that chemically novel, highly selective and efficacious serotonin 5-HT1A receptor agonists — F13714, F15599 and NLX-112 — exhibit favorable activity in pre-clinical tests of levodopa-induced dyskinesia. In particular, NLX-112 potently and completely abolishes levodopa-induced dyskinesia, whereas previously tested serotonergic agonists only achieve a partial reduction. The anti-dyskinetic effect of NLX-112 was maintained upon repeated (daily) administration for two weeks. Notably, NLX-112 does not impair the action of levodopa in the cylinder test. In addition, NLX-112 stimulates rotations in parkinsonian models that have received unilateral 6-OH-DA lesions, suggesting that it may have a motor facilitation effect of its own. The behavioral effects of NLX-112 were abolished by a selective 5-HT1A receptor antagonist and accompanied by neurochemical changes in brain: NLX-112 profoundly reduced 5-HT release, confirming its capacity to silence serotonergic neurons responsible for “false neurotransmitter” dopamine release. Correspondingly, NLX-112 blunts the rapid levodopa-induced increases in dopamine levels, consistent with a capacity to reduce dyskinesia due to inadequate control of dopamine release. Taken together, these results support NLX-112 as a promising clinical candidate to treat levodopa-induced dyskinesia in Parkinson’s disease patients.
Presentations & Publications
Iderberg H., Cenci MA., Varney M., Newman-Tancredi A. Activity of serotonin 5-HT1A receptor biased agonists in rat models of Parkinson’s disease: potential for improved therapeutic management. Society for Neuroscience, Annual Meeting, Nov 9-13, San Diego, California; Poster 63.13.
Iderberg H., Varney M., Cenci MA., Newman-Tancredi A. Preclinical evaluation of selective 5-HT1A biased agonists in the rat model of L-DOPA-induced dyskinesia. 18th Int. Congress of Parkinson's Disease and Movement Disorders, Stockholm, Sweden, June 8-12, 2014
June 2014