The major metabolite of a ghrelin receptor-blocking drug (PF-5190457) itself demonstrates inverse agonist activity at the ghrelin receptor and suppresses food intake in rats.
Biased inverse agonismThe metabolite PF-6870961 shows enhanced potency at blocking β-arrestin recruitment compared to its parent drug, representing a distinct pharmacological profile at the ghrelin receptor.
What the researchers found
PF-6870961, the major hydroxy metabolite of the ghrelin receptor inverse agonist PF-5190457, demonstrated its own binding affinity and inverse agonist activity at GHSR1a. While it had lower binding affinity and potency for blocking inositol phosphate accumulation compared to the parent compound, it showed increased inhibitory potency at β-arrestin recruitment — a form of biased inverse agonism. Intraperitoneal injection suppressed food intake in both male and female rats under food-restricted and ad libitum conditions. Knockout experiments confirmed these effects were mediated specifically through the ghrelin receptor.
Why it matters
Understanding that a drug's metabolite is also pharmacologically active is critical for dosing, safety, and efficacy. The biased inverse agonism of PF-6870961 provides new structure-activity insights that could inform design of improved ghrelin receptor therapeutics for alcohol use disorder and potentially obesity.
How the study worked
The study combined high-throughput screening for off-target interactions, in vitro binding and concentration-response assays at GHSR1a, and in vivo food intake studies in male and female rats. GHSR knockout rats were used to confirm receptor specificity of the metabolite's effects.
What this study cannot tell us
All in vivo experiments were conducted in rats, and the metabolite's effects in humans remain to be characterized. The study focused on food intake as the behavioral readout rather than alcohol consumption, which is the primary clinical target. Pharmacokinetic properties of PF-6870961 in humans are not yet fully established.
How to read the evidence
This is a preclinical pharmacological characterization study combining in vitro assays with in vivo rat experiments and genetic knockout confirmation. It provides strong mechanistic evidence but lacks human clinical data.
When this study was published
Published in 2023, this study builds on a recent phase 1a clinical trial of the parent compound and addresses an active area of addiction therapeutics research.
The bigger picture
The ghrelin system has emerged as a promising therapeutic target for addiction and metabolic disorders. This study deepens our understanding of how drugs targeting this peptide hormone receptor work in the body, revealing that metabolites can have distinct pharmacological profiles that contribute to — and potentially complicate — therapeutic effects.
Questions still open
- Does PF-6870961 contribute to the effects of PF-5190457 on alcohol consumption in humans?
- Could the biased inverse agonism of PF-6870961 be exploited to design more selective ghrelin receptor therapeutics?
- What are the relative plasma concentrations of the parent drug and metabolite in clinical dosing?
Common questions
What is the ghrelin receptor and why is it targeted for alcohol treatment?
What does 'biased inverse agonism' mean?
Read the original research
Initial Pharmacological Characterization of a Major Hydroxy Metabolite of PF-5190457: Inverse Agonist Activity of PF-6870961 at the Ghrelin Receptor.
The Journal of pharmacology and experimental therapeutics, 386(2), 117-128
Citation
Deschaine, Sara L; Hedegaard, Morten A; Pince, Claire L; Farokhnia, Mehdi; Moose, Jacob E; Stock, Ingrid A; Adusumalli, Sravani; Akhlaghi, Fatemeh; Hougland, James L; Sulima, Agnieszka; Rice, Kenner C; Koob, George F; Vendruscolo, Leandro F; Holst, Birgitte; Leggio, Lorenzo. (2023). Initial Pharmacological Characterization of a Major Hydroxy Metabolite of PF-5190457: Inverse Agonist Activity of PF-6870961 at the Ghrelin Receptor.. The Journal of pharmacology and experimental therapeutics, 386(2), 117-128. https://doi.org/10.1124/jpet.122.001393