Pharmacological Characterization of the First in Class Clinical Candidate PF-05190457: a Selective Ghrelin Receptor Competitive Antagonist with Inverse Agonism That Increases Vagal Afferent Firing and Glucose-dependent Insulin Secretion Ex Vivo

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2016 Jan 20

PMID 26784385

Citations 18

Authors

J Kong

J Chuddy

I A Stock

P M Loria

S V Straub

C Vage

K O Cameron

S K Bhattacharya

K Lapham

K F McClure

Y Zhang

V M Jackson

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Ghrelin increases growth hormone secretion, gastric acid secretion, gastric motility and hunger but decreases glucose-dependent insulin secretion and insulin sensitivity in humans. Antagonizing the ghrelin receptor has potential as a therapeutic approach in the treatment of obesity and type 2 diabetes. Therefore, the aim was to pharmacologically characterize the novel small-molecule antagonist PF-05190457 and assess translational pharmacology ex vivo.

Experimental Approach: Radioligand binding in filter and scintillation proximity assay formats were used to evaluate affinity, and europium-labelled GTP to assess functional activity. Rat vagal afferent firing and calcium imaging in dispersed islets were used as native tissues underlying food intake and insulin secretion respectively.

Key Results: PF-05190457 was a potent and selective inverse agonist on constitutively active ghrelin receptors and acted as a competitive antagonist of ghrelin action, with a human Kd of 3 nM requiring 4 h to achieve equilibrium. Potency of PF-05190457 was similar across different species. PF-05190457 increased intracellular calcium within dispersed islets and increased vagal afferent firing in a concentration-dependent manner with similar potency but was threefold less potent as compared with the in vitro Ki in recombinant overexpressing cells. The effect of PF-05190457 on rodent islets was comparable with glibenclamide, but glucose-dependent and additive with the insulin secretagogue glucagon-like peptide-1.

Conclusions And Implications: Together, these data provide the pharmacological in vitro and ex vivo characterization of the first ghrelin receptor inverse agonist, which has advanced into clinical trials to evaluate the therapeutic potential of blocking ghrelin receptors in obesity and type 2 diabetes.

Citing Articles

A randomized, double-blind, placebo-controlled study of a GHSR blocker in people with alcohol use disorder.

Faulkner M, Farokhnia M, Lee M, Farinelli L, Browning B, Abshire K JCI Insight. 2024; 9(24).

PMID: 39704175 PMC: 11665556. DOI: 10.1172/jci.insight.182331.

Initial Pharmacological Characterization of a Major Hydroxy Metabolite of PF-5190457: Inverse Agonist Activity of PF-6870961 at the Ghrelin Receptor.

Deschaine S, Hedegaard M, Pince C, Farokhnia M, Moose J, Stock I J Pharmacol Exp Ther. 2023; 386(2):117-128.

PMID: 36631279 PMC: 10353127. DOI: 10.1124/jpet.122.001393.

The controversial role of the vagus nerve in mediating ghrelin's actions: gut feelings and beyond.

Perello M, Cornejo M, De Francesco P, Fernandez G, Gautron L, Valdivia L IBRO Neurosci Rep. 2022; 12:228-239.

PMID: 35746965 PMC: 9210457. DOI: 10.1016/j.ibneur.2022.03.003.

"Sibling" battle or harmony: crosstalk between nesfatin-1 and ghrelin.

Chen X, Dong J, Jiao Q, Du X, Bi M, Jiang H Cell Mol Life Sci. 2022; 79(3):169.

PMID: 35239020 PMC: 11072372. DOI: 10.1007/s00018-022-04193-6.

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder.

Burnette E, Nieto S, Grodin E, Meredith L, Hurley B, Miotto K Drugs. 2022; 82(3):251-274.

PMID: 35133639 PMC: 8888464. DOI: 10.1007/s40265-021-01670-3.

References

Sakata I, Yamazaki M, Inoue K, Hayashi Y, Kangawa K, Sakai T . Growth hormone secretagogue receptor expression in the cells of the stomach-projected afferent nerve in the rat nodose ganglion. Neurosci Lett. 2003; 342(3):183-6. DOI: 10.1016/s0304-3940(03)00294-5. View

Damjanovic S, Lalic N, Pesko P, Petakov M, Jotic A, Miljic D . Acute effects of ghrelin on insulin secretion and glucose disposal rate in gastrectomized patients. J Clin Endocrinol Metab. 2006; 91(7):2574-81. DOI: 10.1210/jc.2005-1482. View

Gnanapavan S, Kola B, Bustin S, Morris D, McGee P, Fairclough P . The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab. 2002; 87(6):2988. DOI: 10.1210/jcem.87.6.8739. View

Grabauskas G, Wu X, Lu Y, Heldsinger A, Song I, Zhou S . KATP channels in the nodose ganglia mediate the orexigenic actions of ghrelin. J Physiol. 2015; 593(17):3973-89. PMC: 4575581. DOI: 10.1113/JP270788. View

Reimer M, Pacini G, Ahren B . Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinology. 2003; 144(3):916-21. DOI: 10.1210/en.2002-220819. View

Burdyga G, Varro A, Dimaline R, Thompson D, Dockray G . Ghrelin receptors in rat and human nodose ganglia: putative role in regulating CB-1 and MCH receptor abundance. Am J Physiol Gastrointest Liver Physiol. 2006; 290(6):G1289-97. DOI: 10.1152/ajpgi.00543.2005. View

Yakabi K, Kawashima J, Kato S . Ghrelin and gastric acid secretion. World J Gastroenterol. 2008; 14(41):6334-8. PMC: 2766114. DOI: 10.3748/wjg.14.6334. View

Blatnik M, Soderstrom C . A practical guide for the stabilization of acylghrelin in human blood collections. Clin Endocrinol (Oxf). 2010; 74(3):325-31. DOI: 10.1111/j.1365-2265.2010.03916.x. View

Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M . Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab. 2004; 89(6):3062-5. DOI: 10.1210/jc.2003-031964. View

10.

Esler W, Rudolph J, Claus T, Tang W, Barucci N, Brown S . Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology. 2007; 148(11):5175-85. DOI: 10.1210/en.2007-0239. View

11.

Vestergaard E, Gormsen L, Jessen N, Lund S, Hansen T, Moller N . Ghrelin infusion in humans induces acute insulin resistance and lipolysis independent of growth hormone signaling. Diabetes. 2008; 57(12):3205-10. PMC: 2584125. DOI: 10.2337/db08-0025. View

12.

Homaee H, Moradi F, Azarbayjani M, Peeri M . Relationships between acylated ghrelin with growth hormone, insulin resistance, lipid profile, and cardio respiratory function in lean and obese men. J Res Med Sci. 2012; 16(12):1612-8. PMC: 3434904. View

13.

Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N . Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology. 2001; 120(2):337-45. DOI: 10.1053/gast.2001.22158. View

14.

Inui A, Asakawa A, Bowers C, Mantovani G, Laviano A, Meguid M . Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ. FASEB J. 2004; 18(3):439-56. DOI: 10.1096/fj.03-0641rev. View

15.

Schellekens H, Dinan T, Cryan J . Lean mean fat reducing "ghrelin" machine: hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity. Neuropharmacology. 2009; 58(1):2-16. DOI: 10.1016/j.neuropharm.2009.06.024. View

16.

Wierup N, Sundler F . Ultrastructure of islet ghrelin cells in the human fetus. Cell Tissue Res. 2005; 319(3):423-8. DOI: 10.1007/s00441-004-1044-x. View

17.

Patel K, Dixit V, Lee J, Kim J, Schaffer E, Nguyen D . The GHS-R blocker D-[Lys3] GHRP-6 serves as CCR5 chemokine receptor antagonist. Int J Med Sci. 2012; 9(1):51-8. PMC: 3222091. DOI: 10.7150/ijms.9.51. View

18.

Sabbatini F, Melotto S, Bernasconi G, Bromidge S, DAdamo L, Rinaldi M . Azabicyclo[3.1.0]hexane-1-carbohydrazides as potent and selective GHSR1a ligands presenting a specific in vivo behavior. ChemMedChem. 2011; 6(11):1981-5. DOI: 10.1002/cmdc.201100285. View

19.

Burdyga G, Varro A, Dimaline R, Thompson D, Dockray G . Expression of cannabinoid CB1 receptors by vagal afferent neurons: kinetics and role in influencing neurochemical phenotype. Am J Physiol Gastrointest Liver Physiol. 2010; 299(1):G63-9. PMC: 2904113. DOI: 10.1152/ajpgi.00059.2010. View

20.

Pagotto U, Gambineri A, Vicennati V, Heiman M, Tschop M, Pasquali R . Plasma ghrelin, obesity, and the polycystic ovary syndrome: correlation with insulin resistance and androgen levels. J Clin Endocrinol Metab. 2002; 87(12):5625-9. DOI: 10.1210/jc.2002-020776. View