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Your brain is chemical...

Small molecules mediate its communication, maintenance, function and dysfunction. Our lab has published methods to synthesize important classes of CNS-active metabolites including potent nAChR inhibitors and Illicium terpenes, sometimes called ‘neurotrophic terpenes.’  We proposed that these latter metabolites enhance neurite outgrowth through binding to the CysLoop family of neurotransmitter-gated ion channels–probably GABAa receptors. Our chemistry allows us to match the combinatorial nature of these receptors with a combinatorial assembly of terpenes. More recently, we described a computational workflow called CANDOR (Computed Affinity / Dynamically Ordered Retrosynthesis) to rapidly synthesize a stabilized salvinorin A analog that potently and selectively agonizes the kappa opioid receptor (KOR), a target for next generation analgesics and psychotropic therapeutics. This synthesis is being used to generate important KOR agonists, but we anticipate the CANDOR workflow will accelerate the deployment of many other natural product scaffolds in medicinal chemistry campaigns. For example, we recently showed that dynamic retrosynthetic methylation stabilizes the GABAaR antagonist picrotoxinin and increases its structural complexity, but also opens a dramatically shortened, eight-step route.  


See publications:

  1. Crossley, S. W. M.; Tong, G.; Lambrecht, M.; Burdge, H. E.; Shenvi, R. A. Synthesis of Picrotoxinin via Late-Stage Strong Bond Activations, J. Am. Chem. Soc. 2020142, 11376–11381.

  2. Baker, M. A.; Demoret, R. M.; Owtawa, M.; Shenvi, R. A. "Concise Asymmetric Synthesis of Bilobalide," Nature, 2019, 575, 643-646.

  3. Burdge, H. E.; Oguma, T.; Kawajiri, T.; Shenvi, R. A. "Concise synthesis of GB22 by endo-selective siloxycyclopropane arylation," ChemRxiv DOI: 10.26434/chemrxiv.8263415. v1 

  4. Witkin, J. M.; Shenvi, R. A.; Li, X.; Gleason, S. D.; Weiss, J.; Morrow, D.; Catow, J. T.; Wakulchik, M.; Ohtawa, M.; Lu, H.-H.; Martinez, M. D.; Schkeryantz, J. M.; Carpenter, T. S.; Lightstone, F. C.; Cerne, R. "Pharmacological Characterization of the Neurotrophic Sesquiterpene Jiadifenolide Reveals a Non-Convulsant Signature and Potential for Progression in Neurodegenerative Disease Studies." Biochem. Pharmacol. 2018, 155, 61–70. 

  5. Roach, J. R.; Shenvi, R. A. "A Review of Salvinorin Analogs and their Kappa-Opioid Receptor Activity." Bioorg. Med. Chem. Lett. 2018, 28, 1436–1445. 

  6. Hirasawa, S.; Cho, M.; Brust,T. F.; Roach, J. R.; Bohn, L. M.; Shenvi, R. A. "O6C-20-nor-SalA is a stable and potent KOR agonist." Bioorg. Med. Chem. Lett. 2018, 28, 2770–2722. 

  7. Roach, J. J.; Sasano, Y.; Schmid, C. L.; Zaidi, S.; Katrich, V.; Stevens, R. C.; Bohn, L. M.; Shenvi, R. A. "Dynamic Strategic Bond Analysis Yields a 10-step Synthesis of 20-nor-SalA, a Potent κ-OR Agonist," A(CS)20173, 1329–1336.

  8. Ohtawa, M.; Krambis, M.J.; Cerne, R.; Schkeryantz, J.M.; Witkin, J.M.; Shenvi, R.A. "Synthesis of (–)-11-O-debenzoyltashironin: Neurotrophic Sesquiterpenes Cause Hyperexcitation." JACS, 2017, 139, 9637-9644. 

  9. Lu, H.-H.; Martinez, M. D.; Shenvi, R. A. "Eight-Step, Gram-Scale Synthesis of (–)-Jiadifenolide" Nature Chem. 2015, 7, 604-607.

  10. Shenvi, R. A. “Neurite outgrowth enhancement by jiadifenolide: possible targets” Nat. Prod. Rep. 2016, 33, 535-539.

  11. Tabor, M. G.; Shenvi, R. A. "Synthesis of Lepadiformine Using a Hydroamination Transform" Org. Lett. 201517, 5776.

  12. Pronin, S. V.; Tabor, M. G.; Jansen, D. J.; Shenvi, R. A. “A Stereoselective Hydroamination Transform to Access Polysubstituted Indolizidines”, JACS2012, 134, 2012-2015.

Beckman Center for Chemical Sciences

10550 N. Torrey Pines Road

La Jolla, CA   92037

email | phone: 858.784.8415

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