Opioid Receptor Probes Derived from Cycloaddition of the Hallucinogen Natural Product Salvinorin A

• Published in: Journal of natural products (Washington, D.C.) Vol. 74; no. 4; pp. 718 - 726
• Main Authors: Lozama, Anthony, Cunningham, Christopher W, Caspers, Michael J, Douglas, Justin T, Dersch, Christina M, Rothman, Richard B, Prisinzano, Thomas E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society and American Society of Pharmacognosy 25.04.2011; Amer Chemical Soc; American Society of Pharmacognosy
• Subjects: Biological and medical sciences; Chemistry, Medicinal; Diterpenes, Clerodane - chemical synthesis; Diterpenes, Clerodane - chemistry; Diterpenes, Clerodane - pharmacology; Furans - chemistry; Hallucinogens - chemical synthesis; Hallucinogens - chemistry; Hallucinogens - pharmacology; Life Sciences & Biomedicine; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Plant Sciences; Receptors, Opioid, kappa - agonists; Salvia - chemistry; Science & Technology; Stereoisomerism; Structure-Activity Relationship; POTENT; DIELS-ALDER REACTIONS; NEOCLERODANE DITERPENES; FURAN RING; IN-VIVO; SALVIA-DIVINORUM; BIOACTIVATION; IDENTIFICATION; TEUCRIN-A; AGONIST; Terpenoid; Cycloaddition; Structure activity relation; Ligand; Opioid receptor; Diterpene; Diels Alder addition; Lactone; Natural compound; Microwave heating; Chemical synthesis; Operating conditions
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np1007872

As part of our continuing efforts toward more fully understanding the structure−activity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels−Alder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure−activity relationships of furan-containing natural products.