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Picrotoxinin-derived NCEs as Allosteric GABAAR antagonists
The Scripps Research lnstitute
Small molecule
Neurology
Hit To Lead or Lead Optimization
Background
GABA type A (GABAA) receptor (GABAAR) is a ligand-gated chloride ion channel that interacts with its namesake inhibitory neurotransmitter, GABA, and a variety of functional (though not structural) analogs, known collectively as sedatives, barbiturates or depressants.
• Picrotoxane is a family of botanicals that act as non-competitive agonists (NCA)/allosteric modulators of GABAAR. As a tool compound, Picrotoxinin (PXN) can be dosed alone or in a 1:1 mixture with its less active C12 hydrate (Picrotin, PTN) – together known as picrotoxin (PTX). To date, known picrotoxane NCAs are associated with lethal convulsions – a feature absent in the sesquiterpenoids bilobalide & jiadifenolide.
Objective
The Shenvi Lab is engaged in developing efficient synthetic routes to manufacture highly effective and potent psychoactive and psychedelic natural products against important receptors involved in neuropsychiatric diseases. Here, the group is targeting GABAAR with picrotoxane-derived NCAs and their derivatives (new chemical entities (NCEs))
Target Product Profile
• Defined manufacturing route; no reported total synthesis of PXN
• Wider therapeutic window; acute toxicity of PTX at LD50 of 2 mg/kg in rat, i.p.
• Selectivity towards receptor; no PXN analog has demonstrated selectivity
CROSSLEY, Steven W. M, TONG. Guanghu
PCT-US2020-070376 (2020.08.06)
• "Synthesis of (−)-Picrotoxinin by Late-Stage Strong Bond Activation". Crossley, S. W. M., Tong, G. et al. Journal of the American Chemical Society, 2020 142(26), 11376–11381. https://doi.org/10.1021/jacs.0c05042
• "Revision of the unstable picrotoxinin hydrolysis product". Tong, G., & Shenvi, R. A. Angewandte Chemie, 2021 60(35), 19113–19116. https://doi.org/10.1002/anie.202107785
• "Methylation Confers Accessibility, Stability and Selectivity to Picrotoxinin". Tong, G et al. ChemRxiv. Cambridge: Cambridge Open Engage; 2022
