title: Identification of the First Marine-Derived Opioid Receptor "Balanced" Agonist with a Signaling Profile That Resembles the Endorphins.
abstract: Opioid therapeutics are excellent analgesics, whose utility is compromised by dependence. Morphine (1) and its clinically relevant derivatives such as OxyContin (2), Vicodin (3), and Dilaudid (4) are "biased" agonists at the μ opioid receptor (OR), wherein they engage G protein signaling but poorly engage β-arrestin and the endocytic machinery. In contrast, endorphins, the endogenous peptide agonists for ORs, are potent analgesics, show reduced liability for tolerance and dependence, and engage both G protein and β-arrestin pathways as "balanced" agonists. We set out to determine if marine-derived alkaloids could serve as novel OR agonist chemotypes with a signaling profile distinct from morphine and more similar to the endorphins. Screening of 96 sponge-derived extracts followed by LC-MS-based purification to pinpoint the active compounds and subsequent evaluation of a mini library of related alkaloids identified two structural classes that modulate the ORs. These included the following: aaptamine (10), 9-demethyl aaptamine (11), demethyl (oxy)-aaptamine (12) with activity at the δ-OR (EC50: 5.1, 4.1, 2.3 μM, respectively) and fascaplysin (17), and 10-bromo fascaplysin (18) with activity at the μ-OR (EC50: 6.3, 4.2 μM respectively). An in vivo evaluation of 10 using δ-KO mice indicated its previously reported antidepressant-like effects are dependent on the δ-OR. Importantly, 17 functioned as a balanced agonist promoting both G protein signaling and β-arrestin recruitment along with receptor endocytosis similar to the endorphins. Collectively these results demonstrate the burgeoning potential for marine natural products to serve as novel lead compounds for therapeutic targets in neuroscience research.
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.|Department of Natural Sciences and Mathematics, Dominican University of California , San Rafael, California 94901, United States.
authors.forename: Tyler A
authors.initials: TA
authors.lastname: Johnson
authors.affiliation: Department of Neurology, University of California , San Francisco, California 94158, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Milan-Lobo
authors.affiliation: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina , Chapel Hill, North Carolina 27514, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Che
authors.affiliation: Department of Neurology, University of California , San Francisco, California 94158, United States.
authors.forename: Madeline
authors.initials: M
authors.lastname: Ferwerda
authors.affiliation: Department of Natural Sciences and Mathematics, Dominican University of California , San Rafael, California 94901, United States.
authors.forename: Eptisam
authors.initials: E
authors.lastname: Lambu
authors.affiliation: Department of Natural Sciences and Mathematics, Dominican University of California , San Rafael, California 94901, United States.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: McIntosh
authors.affiliation: Department of Neurology, University of California , San Francisco, California 94158, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Neurology, University of California , San Francisco, California 94158, United States.
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Lorig-Roach
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
authors.forename: Phillip
authors.initials: P
authors.lastname: Crews
authors.affiliation: Department of Neurology, University of California , San Francisco, California 94158, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whistler
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D004723:Endorphins / Q000737:chemistry / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009287:Naphthyridines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D011161:Porifera / Q000737:chemistry; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D021241:Spectrometry, Mass, Electrospray Ionization; D013550:Swimming / Q000523:psychology; D000071557:beta-Arrestins / Q000378:metabolism; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines
chemical_list: D000701:Analgesics, Opioid; D000242:Cyclic AMP; D004723:Endorphins; D019204:GTP-Binding Proteins; D007211:Indoles; D009287:Naphthyridines; D017465:Receptors, Opioid, delta; D000071557:beta-Arrestins; C069346:fascaplysine; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines; C043986:aaptamine
keywords: G protein-coupled receptor (GPCR); aaptamine; balanced agonism; biased agonism; dependence; endorphins; fascaplysin; opioid; signaling profile; tolerance