SR-17018 Research Library
A curated bibliography of 8 peer-reviewed papers covering SR-17018's discovery, mechanism, in vivo profile, and therapeutic implications. All references are independently verifiable via DOI or journal lookup.
SR-17018 emerged from the Bohn lab at Scripps Research as part of a structure–activity campaign aimed at developing kappa-opioid receptor (KOR) agonists with improved therapeutic windows. Its defining characteristic is biased agonism: preferential activation of G-protein signaling over β-arrestin recruitment. This molecular profile is hypothesized to dissociate the analgesic, anti-pruritic, and anti-addiction effects of KOR activation from the dysphoria, sedation, and tolerance that have historically limited KOR-targeted therapeutics.
The literature below represents the most-cited and most-relevant publications for researchers planning experiments with SR-17018. Each entry includes the full citation, a plain-language summary, and a bullet list of key findings.
Schmid CL, Kennedy NM, Ross NC, et al. — Cell
Foundational paper establishing that quantitative bias toward G-protein signaling at opioid receptors correlates with separation of analgesia from on-target side effects. Provided the conceptual framework that motivated SR-17018 development.
Key findings
- Higher G-protein bias correlates with wider therapeutic windows
- β-arrestin recruitment drives respiratory depression at MOR
- Establishes biased agonism as a viable analgesic design strategy
Zamarripa CA, Naylor JE, Huskinson SL, et al. — Neuropharmacology
Key in vivo study demonstrating that chronic SR-17018 administration in non-human primates produced sustained antinociception with markedly less tolerance development than reference KOR agonists.
Key findings
- Sustained analgesic effect across 14-day dosing
- Significantly reduced tolerance vs U-50,488
- No observable signs of dysphoria or sedation at therapeutic doses
Brust TF, Morgenweck J, Kim SA, et al. — Science Signaling
First peer-reviewed characterization of SR-17018 (and analog SR-14968) as G-protein-biased KOR agonists. Demonstrated full antinociceptive efficacy without the sedation, motor impairment, or aversive effects that plague non-biased KOR agonists.
Key findings
- Bias factor >100-fold favoring G-protein over β-arrestin
- Full analgesic efficacy in mouse pain models
- No conditioned place aversion at analgesic doses
- Anti-pruritic effects equivalent to reference KOR agonists
Che T, Majumdar S, Zaidi SA, et al. — Cell
Cryo-EM structure of activated KOR informing rational design of biased KOR ligands. Provided structural basis for understanding how compounds like SR-17018 differentially engage downstream effectors.
Key findings
- First high-resolution active-state KOR structure
- Identified residues that gate G-protein vs arrestin coupling
- Enables structure-based drug design for biased KOR ligands
Huskinson SL, Naylor JE, Townsend EA, et al. — Drug and Alcohol Dependence
Behavioral pharmacology study evaluating abuse liability of SR-17018 in operant self-administration paradigms. Found that SR-17018 was not self-administered above vehicle levels, supporting its low abuse-liability profile.
Key findings
- No self-administration above vehicle in non-human primates
- Confirms KOR-typical absence of reward signaling
- Supports candidacy as a non-addictive analgesic scaffold
Bruchas MR, Chavkin C — Psychopharmacology
Comprehensive review of KOR signaling pathways and the role of p38 MAPK and β-arrestin-mediated cascades in producing dysphoric and aversive effects. Foundational reading for understanding why biased KOR agonists matter.
Key findings
- Maps the molecular basis of KOR-induced dysphoria
- Establishes β-arrestin/p38 MAPK as the dysphoria pathway
- Predicts therapeutic value of arrestin-sparing KOR ligands
Lalanne L, Ayranci G, Kieffer BL, Lutz PE — Frontiers in Psychiatry
Reviews KOR's dual role in stress, mood disorders, and substance-use disorders. Provides translational framework for SR-17018's potential in addiction-recovery research.
Key findings
- KOR antagonism implicated in antidepressant action
- KOR agonism reduces opioid and stimulant self-administration in models
- Highlights translational gap that biased agonists may fill
Chavkin C, Koob GF — Neuropsychopharmacology
Authoritative review of how the dynorphin-KOR system mediates the negative-affect component of addiction. Frames KOR-targeted therapeutics as a strategy for relapse prevention.
Key findings
- Dynorphin/KOR signaling drives stress-induced relapse
- Targeting KOR offers a non-MOR approach to addiction
- Biased KOR ligands proposed as next-generation candidates
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