In vitro pharmacology and In vivo neuroprotective effects of CMPI analogues in an optimized Zebrafish model of Parkinsons disease

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Parkinson’s Disease (PD) results from multiple underlying pathologies, including accumulation of a-synuclein- containing Lewy bodies, loss of dopaminergic neurons, and perturbation of other neurotransmitter pathways. While increasing dopamine production using the precursor L-DOAP seems effective at reducing PD symptoms at first, the continuous decline in the number of dopaminergic neurons as PD progresses reduces the effectiveness of L-DOPA, and additional therapy to control the PD's symptoms becomes necessary. The lack of disease-modifying drugs that target PD's underlying pathologies and stop its progression represents a significant gap in our knowledge and unmet clinical need. Therefore, this application aims to initiate early step experiments in a continuum of research that is likely to lead to the development of clinically relevant positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChRs) which are known to have neuroprotective, anti- inflammatory, and precognitive properties and thus hold promise for the development of drugs with disease- modifying properties for PD. In this proposal, we are taking advantage of a lead pharmacophore, CMPI, that we have identified as an (α4)3(β2)2 nAChR-selective PAM and its analogs to develop selective nAChR PAMs and to provide proof-of- concept evidence of their in vivo efficacy against PD. We propose the following specific aims: 1) Identification of CMPI analogs with high potency, efficacy, and selectivity as (α4)3(β2)2 nAChR PAMs; 2A) Optimization of a zebrafish model for in vivo Parkinson’s disease drug screening; and 2B) Assessment of nAChR PAMs effect on behavioral, anatomical, and molecular measures of PD progression. Upon accomplishing these specific aims, we expect that CMPI analogs that bind with high affinity and selectivity to and potentiate agonist-induced responses of (α4)3(β2)2 nAChR will be identified. The anticipated results will also provide in vivo evidence to support the pharmacological merit of α4β2 nAChR PAMs as a novel strategy to slow the progression of motor and cognitive decline associated with PD. The proposed research project will also optimize conditions for a reliable zebrafish PD-like phenotype animal model with measurable behavioral, anatomical, and biological readouts suitable for high throughput screening of novel therapeutic compounds for PD. This model will help reduce the time and cost of selecting lead compounds for future animal and human studies and facilitate the development of novel therapeutics for the treatment of motor symptoms and cognitive decline associated with Parkinson’s disease. Once such drugs become clinically relevant, progress will have been made toward effective PD treatment and advancing the National Institutes of Health mission.