Discovery of CVN417, a Novel Brain-Penetrant α6-Containing Nicotinic Receptor Antagonist for the Modulation of Motor Dysfunction

Nicotinic acetylcholine receptor (nAChR) α6 subunit
RNA expression
is relatively restricted to midbrain regions and is located presynaptically
on dopaminergic neurons projecting to the striatum. This subunit modulates
dopamine neurotransmission and may have therapeutic potential in movement
disorders. We aimed to develop potent and selective α6-containing
nAChR antagonists to explore modulation of dopamine release and regulation
of motor function in vivo. High-throughput screening (HTS) identified
novel α6-containing nAChR antagonists and led to the development
of CVN417. This molecule blocks α6-containing nAChR
activity in recombinant cells and reduces firing frequency of noradrenergic
neurons in the rodent locus coeruleus. CVN417 modulated
phasic dopaminergic neurotransmission in an impulse-dependent manner.
In a rodent model of resting tremor, CVN417 attenuated
this behavioral phenotype. These data suggest that selective antagonism
of α6-containing nAChR, with molecules such as CVN417, may have therapeutic utility in treating the movement dysfunctions
observed in conditions such as Parkinson’s disease.

烟碱型乙酰胆碱受体（nAChR）α6亚基的RNA表达相对局限于中脑区域，并位于投射至纹状体的多巴胺能神经元的前突触部位。该亚基调节多巴胺神经传递，并可能在运动障碍的治疗中具有潜在价值。本研究旨在开发强效且选择性的含α6亚基的nAChR拮抗剂，以探索其对多巴胺释放的调节以及对体内运动功能的调控。高通量筛选（HTS）鉴定了新型含α6亚基的nAChR拮抗剂，并促进了CVN417的研发。该分子可阻断重组细胞中含α6亚基的nAChR的活性，并降低啮齿动物黑质致密部中肾上腺素能神经元的放电频率。CVN417以脉冲依赖的方式调节周期性的多巴胺神经传递。在啮齿动物的静止震颤模型中，CVN417减轻了这一行为表型。这些数据表明，针对α6亚基的nAChR的选择性拮抗，如CVN417，在治疗帕金森病等条件下观察到的运动功能障碍中可能具有治疗效用。