Identification of the First Marine-Derived Opioid Receptor "Balanced" Agonist with a Signaling Profile That Resembles the Endorphins

Tyler A. Johnson; Laura Millan-Lobo; Tao Che; Madeline Ferwerda; Eptisam Lambu; Nicole L. McIntosh; Fei Li; Li He; Nicholas Lorig-Roach; Phillip Crews; Jennifer L. Whistler

doi:10.1021/acschemneuro.6b00167

Identification of the First Marine-Derived Opioid Receptor "Balanced" Agonist with a Signaling Profile That Resembles the Endorphins

Tyler A. Johnson
, Laura Millan-Lobo
, Tao Che
, Madeline Ferwerda
, Eptisam Lambu
, Nicole L. McIntosh
, Fei Li
, Li He
, Nicholas Lorig-Roach
, Phillip Crews
, Jennifer L. Whistler

Department of Natural Sciences and Mathematics

Department of Neurology, University of California, San Francisco
National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina, Chapel Hill
Student, Dominican University of California
Department of Chemistry and Biochemistry, University of California, Santa Cruz

Research output: Contribution to journal › Article › peer-review

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 (EC

Original language	American English
Pages (from-to)	473-485
Number of pages	13
Journal	ACS Chemical Neuroscience
Volume	8
Issue number	3
DOIs	https://doi.org/10.1021/acschemneuro.6b00167
State	Published - Oct 17 2016

Funding

We thank Carsten K. Nielsen and Selena Bartlett for assistance in screening compounds (10−20). T.A.J. thanks David Barnes for inspiring philosophical discussions related to the power of the endorphins. This work was supported by grants from the NIH, R01DA019958 (J.L.W.), R01DA015232 (J.L.W.), R21DA031574 (J.L.W.), R01CA47135 (P.C.), NSF MS Instrument Grant UCSC CHE-147922 (P.C.), and the Fletcher Jones Fund of Dominican University of California (T.A.J.).

Funders	Funder number
National Science Foundation	UCSC CHE-147922
National Institutes of Health	R21DA031574, R01CA47135, R01DA019958
National Institute on Drug Abuse	R01DA015232

Keywords

Analgesics
Opioid
Animals
Computer Simulation
Cyclic AMP
Endocytosis
Endorphins
GTP-Binding Proteins
HEK293 Cells
Humans
Indoles
Locomotion
Male
Mice
Transgenic
Models
Molecular
Naphthyridines
Porifera
Receptors
delta
Signal Transduction
Spectrometry
Mass
Electrospray Ionization
Swimming
beta-Arrestins

Disciplines

Biochemistry
Natural Products Chemistry and Pharmacognosy

Access to Document

10.1021/acschemneuro.6b00167

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Cite this

Johnson, T. A., Millan-Lobo, L., Che, T., Ferwerda, M., Lambu, E., McIntosh, N. L., Li, F., He, L., Lorig-Roach, N., Crews, P., & Whistler, J. L. (2016). Identification of the First Marine-Derived Opioid Receptor "Balanced" Agonist with a Signaling Profile That Resembles the Endorphins. ACS Chemical Neuroscience, 8(3), 473-485. https://doi.org/10.1021/acschemneuro.6b00167

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AU - Ferwerda, Madeline

AU - Lambu, Eptisam

AU - McIntosh, Nicole L.

AU - Li, Fei

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Identification of the First Marine-Derived Opioid Receptor "Balanced" Agonist with a Signaling Profile That Resembles the Endorphins

Abstract

Funding

Keywords

Disciplines

Access to Document

OpenUrl availability

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