2. Academic Validation
  3. Discovery of CVN417, a Novel Brain-Penetrant α6-Containing Nicotinic Receptor Antagonist for the Modulation of Motor Dysfunction

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

  • J Med Chem. 2023 Sep 14;66(17):11718-11731. doi: 10.1021/acs.jmedchem.3c00630.
Louisa A Christie 1 2,  Nicola L Brice 1 2,  Anna Rowland 1 2,  Louise Dickson 1 2,  Rishi Anand 3,  Martin Teall 1 2,  Kevin J Doyle 1,  Lakshminarayana Narayana 4,  Christine Mitchell 2,  Jenna R M Harvey 1 2,  Victoria Mulligan 1 2,  Lee A Dawson 1,  Stephanie J Cragg 3,  Mark Carlton 1 2,  Roland W Bürli 1
Affiliations

Affiliations

  • 1 Cerevance Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, United Kingdom.
  • 2 Takeda Cambridge Limited, 418 Cambridge Science Park, Cambridge CB4 0PZ, United Kingdom.
  • 3 Centre for Cellular and Molecular Neurobiology, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.
  • 4 Aragen Lifesciences Limited, Plot #284A (part), Bommasandra-Jigani Link Road Industrial Area, Bengaluru 562106, India.
PMID: 37651656 DOI: 10.1021/acs.jmedchem.3c00630
Abstract

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.

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