Initial Pharmacological Characterization of a Major Hydroxy Metabolite of PF-5190457: Inverse Agonist Activity of PF-6870961 at the Ghrelin Receptor
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Preclinical and clinical studies have identified the ghrelin receptor [growth hormone secretagogue receptor (GHSR)1a] as a potential target for treating alcohol use disorder. A recent phase 1a clinical trial of a GHSR1a antagonist/inverse agonist, PF-5190457, in individuals with heavy alcohol drinking identified a previously undetected major hydroxy metabolite of PF-5190457, namely PF-6870961. Here, we further characterized PF-6870961 by screening for off-target interactions in a high-throughput screen and determined its in vitro pharmacodynamic profile at GHSR1a through binding and concentration-response assays. Moreover, we determined whether the metabolite demonstrated an in vivo effect by assessing effects on food intake in male and female rats. We found that PF-6870961 had no off-target interactions and demonstrated both binding affinity and inverse agonist activity at GHSR1a. In comparison with its parent compound, PF-5190457, the metabolite PF-6870961 had lower binding affinity and potency at inhibiting GHSR1a-induced inositol phosphate accumulation. However, PF-6870961 had increased inhibitory potency at GHSR1a-induced b-arrestin recruitment relative to its parent compound. Intraperitoneal injection of PF-6870961 suppressed food intake under conditions of both food restriction and with ad libitum access to food in male and female rats, demonstrating in vivo activity. The effects of PF-6870961 on food intake were abolished in male and female rats knockout for GHSR, thus demonstrating that its effects on food intake are in fact mediated by the GHSR receptor. Our findings indicate that the newly discovered major hydroxy metabolite of PF-5190457 may contribute to the overall activity of PF-5190457 by demonstrating inhibitory activity at GHSR1a.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Journal of Pharmacology and Experimental Therapeutics |
| Vol/bind | 386 |
| Udgave nummer | 2 |
| Sider (fra-til) | 117-128 |
| Antal sider | 12 |
| ISSN | 0022-3565 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This work was funded by National Institutes of Health National Institute on Drug Abuse (NIDA) Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research (joint Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section) (to L.L.), NIDA Neurobiology of Addiction Section (to G.F.K.), and NIDA/NIAAA joint Drug Design and Synthesis Section (to K.C.R.). Parts of this work were also funded by National Center for Advancing Translational Sciences (NCATS) under a UH2/UH3 grant [Grant TR000963] (to L.L., F.A.) and National Institute of General Medical Sciences (NIGMS) [Grant R01GM134102] (to J.L.H.). We also received support from the NIDA Intramural Research Program Medication Development Program. Dr. Ingrid Stock is a Pfizer employee. Pfizer did not have any role in the study design, execution, or interpretation of the results, and this publication does not necessarily represent the official views of Pfizer. The authors declare that they have no conflicts of interest. dx.doi.org/10.1124/jpet.122.001393.
Funding Information:
This work was funded by National Institutes of Health National Institute on Drug Abuse (NIDA) Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research (joint Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section) (to L.L.), NIDA Neurobiology of Addiction Section (to G.F.K.), and NIDA/NIAAA joint Drug Design and Synthesis Section (to K.C.R.). Parts of this work were also funded by National Center for Advancing Translational Sciences (NCATS) under a UH2/UH3 grant [Grant TR000963] (to L.L., F.A.) and National Institute of General Medical Sciences (NIGMS) [Grant R01GM134102] (to J.L.H.). We also received support from the NIDA Intramural Research Program Medication Development Program. Dr. Ingrid Stock is a Pfizer employee. Pfizer did not have any role in the study design, execution, or interpretation of the results, and this publication does not necessarily represent the official views of Pfizer.
Publisher Copyright:
U.S. Government work not protected by U.S. copyright.
ID: 362059614