Scalable and modular synthesis enables pharmacological diversification of salvinorins

Khan, M. I. H., Sawyer, B. J., Akins, N. S. & Le, H. V. A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse. Eur. J. Med. Chem. 243, 114785 (2022).

Ortega, A., Blount, J. F. & Manchand, P. S. Salvinorin, a new trans-neoclerodane diterpene from Salvia divinorum (Labiatae). J. Chem. Soc. Perkin Trans. 1 1982, 2505–2508 (1982).

Valdes, L. J. III, Butler, W. M., Hatfield, G. M., Paul, A. G. & Koreeda, M. Divinorin A, a psychotropic terpenoid, and divinorin B from the hallucinogenic Mexican mint, Salvia divinorum. J. Org. Chem. 49, 4716–4720 (1984).

Roth, B. L. et al. Salvinorin A: A potent naturally occurring nonnitrogenous κ opioid selective agonist. Proc. Natl Acad. Sci. USA 99, 11934–11939 (2002).

Yan, F. et al. Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to κ-opioid receptors. Biochemistry 44, 8643–8651 (2005).

Béguin, C. et al. Synthesis and in vitro evaluation of salvinorin A analogues: Effect of configuration at C(2) and substitution at C(18). Bioorg. Med. Chem. Lett. 16, 4679–4685 (2006).

Hooker, J. M. et al. Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of effects in humans. NeuroImage 41, 1044–1050 (2008).

Vardy, E. et al. A new DREADD facilitates the multiplexed chemogenetic interrogation of behavior. Neuron 86, 936–946 (2015).

Marchant, N. J. et al. Behavioral and physiological effects of a novel kappa-opioid receptor-based DREADD in rats. Neuropsychopharmacology 41, 402–409 (2016).

Dykstra, L. A., Gmerek, D. E., Winger, G. & Woods, J. H. Kappa opioids in rhesus monkeys. I. Diuresis, sedation, analgesia and discriminative stimulus effects. J. Pharmacol. Exp. Ther. 242, 413–420 (1987).

Wee, S. & Koob, G. F. The role of the dynorphin-κ opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology 210, 121–135 (2010).

Land, B. B. et al. The dysphoric component of stress is encoded by activation of the dynorphin κ-opioid system. J. Neurosci. 28, 407–414 (2008).

Pfeiffer, A., Brantl, V., Herz, A. & Emrich, H. M. Psychotomimesis mediated by κ opiate receptors. Science 233, 774–776 (1986).

MacLean, K. A., Johnson, M. W., Reissig, C. J., Prisinzano, T. E. & Griffiths, R. R. Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects. Psychopharmacology 226, 381–392 (2013).

Schmidt, M. S. et al. Determination of salvinorin A in body fluids by high performance liquid chromatography-atmospheric pressure chemical ionization. J. Chromatogr. B 818, 221–225 (2005).

Tsujikawa, K. et al. In vitro stability and metabolism of salvinorin A in rat plasma. Xenobiotica 39, 391–398 (2009).

Roach, J. J. & Shenvi, R. A. A review of salvinorin analogs and their kappa-opioid receptor activity. Bioorg. Med. Chem. Lett. 28, 1436–1445 (2018).

Prisinzano, T. E. & Rothman, R. B. Salvinorin A analogs as probes in opioid pharmacology. Chem. Rev. 108, 1732–1743 (2008).

Wang, Y. et al. 2-Ethoxymethyl salvinorin B and related 2-alkoxymethyl ethers. Bioorg. Med. Chem. 16, 1279–1286 (2008).

Riley, A. P. et al. Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues. J. Med. Chem. 57, 10464–10475 (2014).

Scheerer, J. R., Lawrence, J. F., Wang, G. C. & Evans, D. A. Asymmetric synthesis of salvinorin A, a potent κ opioid receptor agonist. J. Am. Chem. Soc. 129, 8968–8969 (2007).

Nozawa, M., Suka, Y., Hoshi, T., Suzuki, T. & Hagiwara, H. Total synthesis of the hallucinogenic neoclerodane diterpenoid salvinorin A. Org. Lett. 10, 1365–1368 (2008).

Hagiwara, H., Suka, Y., Nojima, T., Hoshi, T. & Suzuki, T. Second-generation synthesis of salvinorin A. Tetrahedron 65, 4820–4825 (2009).

Line, N. J., Burns, A. C., Butler, S. C., Casbohm, J. & Forsyth, C. J. Total synthesis of (−)-salvinorin A. Chem. Eur. J. 22, 17983–17986 (2016).

Wang, Y. & Metz, P. Total synthesis of the neoclerodane diterpene salvinorin A via an intramolecular Diels–Alder strategy. Org. Lett. 20, 3418–3421 (2018).

Zimdars, P., Wang, Y. & Metz, P. A protecting-group-free synthesis of (−)-salvinorin A. Chem. Eur. J. 27, 7968–7973 (2021).

Halang, M. & Maier, M. E. Formal total synthesis of salvinorin A. 《ChemistryOpen》 11, e202200015 (2022).

Tran, H., McGee, P. & Barriault, L. Formal synthesis of (±)-salvinorin A via gold(I) catalysis. Chem. Eur. J. 29, e202301640 (2023).

Roach, J. J. et al. Dynamic strategic bond analysis yields a ten-step synthesis of 20-nor-salvinorin A, a potent κ-OR agonist. ACS Cent. Sci. 3, 1329–1336 (2017).

Hill, S. J. et al. A route to potent, selective, and biased salvinorin chemical space. ACS Cent. Sci. 9, 1567–1574 (2023).

Han, J. et al. Ligand and G-protein selectivity in the κ-opioid receptor. Nature 617, 417–425 (2023).

Zhao, Y. et al. Structural characterization of kappa-opioid receptor dimer in complex with two G proteins. Nat. Commun. 17, 6980 (2026).

Li, Z. et al. Decoding the κ opioid receptor (KOR): Advancements in structural understanding and implications for opioid analgesic development. Molecules 29, 2635 (2024).

Vardy, E. et al. Chemotype-selective modes of action of κ-opioid receptor agonists. J. Biol. Chem. 288, 34470–34483 (2013).

Vortherms, T. A., Mosier, P. D., Westkaemper, R. B. & Roth, B. L. Differential helical orientations among related G protein-coupled receptors provide a novel mechanism for selectivity. J. Biol. Chem. 282, 3146–3156 (2007).

Wang, Y. et al. 2-Methoxymethyl-salvinorin B is a potent κ opioid receptor agonist with longer lasting action in vivo than salvinorin A. J. Pharmacol. Exp. Ther. 324, 1073–1083 (2008).

Marcune, B. F., Karady, S., Dolling, U.-H. & Novak, T. J. Methoxymethylation of alcohols, phenols, and avermectin aglycones using MOM-2-pyridylsulfide. J. Org. Chem. 64, 2446–2449 (1999).

Chen, H. et al. Total synthesis of (+)-mutilin: a transannular [2+2] cycloaddition/fragmentation approach. J. Am. Chem. Soc. 144, 15462–15467 (2022).

Hoppe, H.-W., Stammen, B., Werner, U., Stein, H. & Welzel, P. An approach to bufadienolides from deoxycholic acid. Reactions of a steroidal α,β-unsaturated aldehyde with some O-silylated ketene acetals. Tetrahedron 45, 3695–3710 (1989).

Shimo, T., Yasuda, M., Tajima, J. & Somekawa, K. Intramolecular photoreactions of 4-(ω-alkenyloxy)-6-methyl-2-pyrones. J. Heterocycl. Chem. 28, 745–748 (1991).

Weber, B. & Seebach, D. Ti-TADDOLate-catalyzed, highly enantioselective addition of alkyl- and aryl-titanium derivatives to aldehydes. Tetrahedron 50, 7473–7484 (1994).

Matsuda, A., Ushimaru, T., Kobayashi, Y. & Harada, T. Catalytic enantioselective arylation and heteroarylation of ketones with organotitanium reagents generated in situ. Chem. Eur. J. 23, 8605–8609 (2017).

Muratspahic, E. et al. Design and structural validation of peptide–drug conjugate ligands of the kappa-opioid receptor. Nat. Commun. 14, 8064 (2023).

Doering, N. P. et al. Mechanistic insights into G protein-biased κ-opioid receptor signaling using dual-charged naltrexamine amides. J. Med. Chem. 69, 3833–3851 (2026).

Uprety, R. et al. Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site. eLife 10, e56519 (2021).

El Daibani, A. et al. Molecular mechanism of biased signaling at the kappa opioid receptor. Nat. Commun. 14, 1338 (2023).

Faridoon, Ng, R., Zhang, G. & Li, J. J. An update on the discovery and development of reversible covalent inhibitors. Med. Chem. Res. 32, 1039–1062 (2023).

Leeson, P. D. & Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discov. 6, 881–890 (2007).

Waring, M. J. Lipophilicity in drug discovery. Expert Opin. Drug Discov. 5, 235–248 (2010).

Fleming, F. F., Yao, L., Ravikumar, P. C., Funk, L. & Shook, B. C. Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore. J. Med. Chem. 53, 7902–7917 (2010).

Wissner, A. et al. 4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors. J. Med. Chem. 43, 3244–3256 (2000).

Li, W. et al. Metabolic activation of furan moiety makes Diosbulbin B hepatotoxic. Arch. Toxicol. 90, 863–872 (2016).

Kawai, K. et al. Design, synthesis, and structure–activity relationship of novel opioid κ-agonists. Bioorg. Med. Chem. 16, 9188–9201 (2008).

Ballesteros, J. A. & Weinstein, H. Integrated methods for the construction of three-dimensional models and computational probing of structure–function relations in G protein-coupled receptors. Methods in Neurosciences, Vol. 25: Receptor Molecular Biology 366–428 (Academic Press, 1995).

Wang, Y. et al. Structures of the entire human opioid receptor family. Cell 186, 413–427.e17 (2023).

Meltzer, R. H. et al. Electrostatic steering at acetylcholine binding sites. Biophys. J. 91, 1302–1314 (2006).

Paton, K. F. et al. The analgesic and anti-inflammatory effects of salvinorin A analogue β-tetrahydropyran salvinorin B in mice. Eur. J. Pain 21, 1039–1050 (2017).

Le Bars, D., Gozariu, M. & Cadden, S. W. Animal models of nociception. Pharmacol. Rev. 53, 597–652 (2001).

Seelig, A. The role of size and charge for blood–brain barrier permeation of drugs and fatty acids. J. Mol. Neurosci. 33, 32–41 (2007).

Pardridge, W. M. Transport of small molecules through the blood–brain barrier: biology and methodology. Adv. Drug Deliv. Rev. 15, 5–36 (1995).

Munro, T. A. et al. Long-acting κ opioid antagonists nor-BNI, GNTI and JDTic: pharmacokinetics in mice and lipophilicity. BMC Pharmacol. 12, 5 (2012).

Vauquelin, G. Effects of target binding kinetics on in vivo drug efficacy: koff, kon and rebinding. Br. J. Pharmacol. 173, 2319–2334 (2016).

Trapp, S., Rosania, G. R., Horobin, R. W. & Kornhuber, J. Quantitative modeling of selective lysosomal targeting for drug design. Eur. Biophys. J. 37, 1317–1328 (2008).

Zürrer, W. E., Wettstein, L., Aicher, H. D., Scheidegger, M. & Ineichen, B. V. The translational potential of salvinorin A: systematic review and meta-analysis of preclinical studies. Transl. Psychiatry 15, 401 (2025).

Keasling, A. W. & Zjawiony, J. K. The plant Salvia divinorum (Lamiaceae)—chemistry and pharmacology. Neuropathology of Drug Addictions and Substance Misuse 551–560 (Elsevier, 2016).

Cunningham, C. W., Rothman, R. B. & Prisinzano, T. E. Neuropharmacology of the naturally occurring κ-opioid hallucinogen salvinorin A. Pharmacol. Rev. 63, 316–347 (2011).

Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis (Wiley-Interscience, 1995).

Wright, S. C. et al. GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics. Nat. Commun. 14, 6243 (2023).

Radoux-Mergault, A., Oberhauser, L., Aureli, S., Gervasio, F. L. & Stoeber, M. Subcellular location defines GPCR signal transduction. Sci. Adv. 9, eadf6059 (2023).

Klein Herenbrink, C. et al. The role of kinetic context in apparent biased agonism at GPCRs. Nat. Commun. 7, 10842 (2016).

Sykes, D. A. et al. The influence of receptor kinetics on the onset and duration of action and the therapeutic index of NVA237 and tiotropium. J. Pharmacol. Exp. Ther. 343, 520–528 (2012).

Sykes, D. A. et al. Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nat. Commun. 8, 763 (2017).

Wang, X. et al. Antinociceptive and antipruritic effects of HSK21542, a peripherally-restricted kappa opioid receptor agonist, in animal models of pain and itch. Front. Pharmacol. 12, 773204 (2021).

Butelman, E. R. & Kreek, M. J. Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders. Front. Pharmacol. 6, 190 (2015).