Developing a Biased Unmatched Bivalent Ligand (BUmBL) Design Strategy to Target the GPCR Homodimer Allosteric Signaling (cAMP over β-Arrestin 2 Recruitment) Within the Melanocortin Receptors

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2018 Apr 19

PMID 29669202

Citations 10

Authors

Cody J Lensing

Katie T Freeman

Sathya M Schnell

Robert C Speth

Adam T Zarth

Carrie Haskell-Luevano

Affiliations

Soon will be listed here.

Abstract

Understanding the functional relevance of G protein-coupled receptor (GPCR) homodimerization has been limited by the insufficient tools to assess asymmetric signaling occurring within dimers comprised of the same receptor type. We present unmatched bivalent ligands (UmBLs) to study the asymmetric function of melanocortin homodimers. UmBLs contain one agonist and one antagonist pharmacophore designed to target a melanocortin homodimer such that one receptor is occupied by an agonist and the other receptor by an antagonist pharmacophore. First-in-class biased UmBLs (BUmBLs) targeting the human melanocortin-4 receptor (hMC4R) were discovered. The BUmBLs displayed biased agonism by potently stimulating cAMP signaling (EC ∼ 2-6 nM) but minimally activating the β-arrestin recruitment pathway (≤55% maximum signal at 10 μM). To our knowledge, we report the first single-compound strategy to pharmacologically target melanocortin receptor allosteric signaling that occurs between homodimers that can be applied straightforwardly in vitro and in vivo to other GPCR systems.

Citing Articles

Ligand-Induced Biased Activation of GPCRs: Recent Advances and New Directions from In Silico Approaches.

Hashem S, Dougha A, Tuffery P Molecules. 2025; 30(5).

PMID: 40076272 PMC: 11901715. DOI: 10.3390/molecules30051047.

Rare variants in the melanocortin 4 receptor gene (MC4R) are associated with abdominal fat and insulin resistance in youth with obesity.

Galuppo B, Mannam P, Bonet J, Pierpont B, Trico D, Haskell-Luevano C Int J Obes (Lond). 2024; .

PMID: 39738493 DOI: 10.1038/s41366-024-01706-0.

Incorporation of Three Extracyclic Arginine Residues into a Melanocortin Macrocyclic Agonist (c[Pro-His-DPhe-Arg-Trp-Dap-Lys(Arg-Arg-Arg-Ac)-DPro]) Decreases Food Intake When Administered Intrathecally or Subcutaneously Compared to a Macrocyclic....

Ericson M, Freeman K, Larson C, Bouchard J, John K, Lunzer M ACS Pharmacol Transl Sci. 2024; 7(4):1114-1125.

PMID: 38633589 PMC: 11020072. DOI: 10.1021/acsptsci.4c00011.

The Parallel Structure-Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands.

Ericson M, Freeman K, Lavoi T, Donow H, Santos R, Giulianotti M Int J Mol Sci. 2023; 24(12).

PMID: 37373293 PMC: 10299128. DOI: 10.3390/ijms241210145.

Discovery of a Pan-Melanocortin Receptor Antagonist [Ac-DPhe(pI)-Arg-Nal(2')-Orn-NH] at the MC1R, MC3R, MC4R, and MC5R that Mediates an Increased Feeding Response in Mice and a 40-Fold Selective MC1R Antagonist [Ac-DPhe(pI)-DArg-Nal(2')-Arg-NH].

Ericson M, Tran L, Mathre S, Freeman K, Holdaway K, John K J Med Chem. 2023; 66(12):8103-8117.

PMID: 37307241 PMC: 10631449. DOI: 10.1021/acs.jmedchem.3c00432.

References

Fleming K, Ericson M, Freeman K, Adank D, Lunzer M, Wilber S . Structure-Activity Relationship Studies of a Macrocyclic AGRP-Mimetic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro] Yield Potent and Selective Melanocortin-4 Receptor Antagonists and Melanocortin-5 Receptor Inverse Agonists That Increase Food Intake.... ACS Chem Neurosci. 2018; 9(5):1141-1151. PMC: 5955836. DOI: 10.1021/acschemneuro.7b00495. View

Shinyama H, Masuzaki H, Fang H, Flier J . Regulation of melanocortin-4 receptor signaling: agonist-mediated desensitization and internalization. Endocrinology. 2003; 144(4):1301-14. DOI: 10.1210/en.2002-220931. View

Portoghese P, Akgun E, Lunzer M . Heteromer Induction: An Approach to Unique Pharmacology?. ACS Chem Neurosci. 2017; 8(3):426-428. DOI: 10.1021/acschemneuro.7b00002. View

DeBoer M, Marks D . Cachexia: lessons from melanocortin antagonism. Trends Endocrinol Metab. 2006; 17(5):199-204. DOI: 10.1016/j.tem.2006.05.005. View

Dehigaspitiya D, Anglin B, Smith K, Weber C, Lynch R, Mash E . Linear scaffolds for multivalent targeting of melanocortin receptors. Org Biomol Chem. 2015; 13(47):11507-17. DOI: 10.1039/c5ob01779c. View

Ferre S, Casado V, Devi L, Filizola M, Jockers R, Lohse M . G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev. 2014; 66(2):413-34. PMC: 3973609. DOI: 10.1124/pr.113.008052. View

Kuhhorn J, Gotz A, Hubner H, Thompson D, Whistler J, Gmeiner P . Development of a bivalent dopamine D₂ receptor agonist. J Med Chem. 2011; 54(22):7911-9. DOI: 10.1021/jm2009919. View

Dehigaspitiya D, Navath S, Weber C, Lynch R, Mash E . Synthesis and bioactivity of MSH4 oligomers prepared by an A + B strategy. Tetrahedron Lett. 2015; 56(23):3060-3065. PMC: 4480789. DOI: 10.1016/j.tetlet.2014.12.022. View

Akgun E, Javed M, Lunzer M, Powers M, Sham Y, Watanabe Y . Inhibition of Inflammatory and Neuropathic Pain by Targeting a Mu Opioid Receptor/Chemokine Receptor5 Heteromer (MOR-CCR5). J Med Chem. 2015; 58(21):8647-57. PMC: 5055304. DOI: 10.1021/acs.jmedchem.5b01245. View

10.

Chen A, Marsh D, Trumbauer M, Frazier E, Guan X, Yu H . Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet. 2000; 26(1):97-102. DOI: 10.1038/79254. View

11.

Hlavackova V, Goudet C, Kniazeff J, Zikova A, Maurel D, Vol C . Evidence for a single heptahelical domain being turned on upon activation of a dimeric GPCR. EMBO J. 2005; 24(3):499-509. PMC: 548662. DOI: 10.1038/sj.emboj.7600557. View

12.

Giuliani D, Bitto A, Galantucci M, Zaffe D, Ottani A, Irrera N . Melanocortins protect against progression of Alzheimer's disease in triple-transgenic mice by targeting multiple pathophysiological pathways. Neurobiol Aging. 2013; 35(3):537-47. DOI: 10.1016/j.neurobiolaging.2013.08.030. View

13.

Xiang Z, Proneth B, Dirain M, Litherland S, Haskell-Luevano C . Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist. Biochemistry. 2010; 49(22):4583-600. PMC: 2888279. DOI: 10.1021/bi100068u. View

14.

Pin J, Kniazeff J, Liu J, Binet V, Goudet C, Rondard P . Allosteric functioning of dimeric class C G-protein-coupled receptors. FEBS J. 2005; 272(12):2947-55. DOI: 10.1111/j.1742-4658.2005.04728.x. View

15.

Takeyasu K, Uchida S, Wada A, Maruno M, Lai R, Hata F . Experimental evidence and dynamic aspects of spare receptor. Life Sci. 1979; 25(20):1761-71. DOI: 10.1016/0024-3205(79)90480-6. View

16.

Sawyer T, Sanfilippo P, Hruby V, Engel M, Heward C, Burnett J . 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. Proc Natl Acad Sci U S A. 1980; 77(10):5754-8. PMC: 350149. DOI: 10.1073/pnas.77.10.5754. View

17.

Josan J, Vagner J, Handl H, Sankaranarayanan R, Gillies R, Hruby V . Solid-Phase Synthesis of Heterobivalent Ligands Targeted to Melanocortin and Cholecystokinin Receptors. Int J Pept Res Ther. 2009; 14(4):293-300. PMC: 2732021. DOI: 10.1007/s10989-008-9150-3. View

18.

Marsh D, Hollopeter G, Huszar D, Laufer R, Yagaloff K, Fisher S . Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat Genet. 1999; 21(1):119-22. DOI: 10.1038/5070. View

19.

Yang Z, Tao Y . Biased signaling initiated by agouti-related peptide through human melanocortin-3 and -4 receptors. Biochim Biophys Acta. 2016; 1862(9):1485-94. DOI: 10.1016/j.bbadis.2016.05.008. View

20.

Le Naour M, Lunzer M, Powers M, Kalyuzhny A, Benneyworth M, Thomas M . Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects. J Med Chem. 2014; 57(15):6383-92. PMC: 4136663. DOI: 10.1021/jm500159d. View