Isoquinoline small molecule ligands are agonists and probe-dependent allosteric modulators of the glucagon subfamily of GPCRs

[Display omitted] Class B1 G protein-coupled receptors (GPCRs) are peptide hormone receptors and well validated therapeutic targets, however development of non-peptide drugs targeting this class of receptors is challenging. Recently, a series of isoquinoline-based derivates were reported in the pate...

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Published in:	Biochemical pharmacology Vol. 229; p. 116483
Main Authors:	Yuliantie, Elita, NH Trinh, Phuc, Hick, Caroline, Ebenhoch, Rebecca, Nar, Herbert, Weichert, Dietmar, Christopoulos, Arthur, M Sexton, Patrick, Wootten, Denise
Format:	Journal Article
Language:	English
Published:	England Elsevier Inc 01-11-2024
Subjects:	Allosteric modulation Allosteric Regulation - drug effects Allosteric Regulation - physiology Animals CHO Cells class B1 GPCRs Cricetulus CTR GCGR GIPR GLP1R Glucagon - agonists Glucagon - chemistry Glucagon - metabolism Glucagon-Like Peptide-1 Receptor - agonists Glucagon-Like Peptide-1 Receptor - metabolism HEK293 Cells Humans Isoquinolines - chemistry Isoquinolines - pharmacology Ligands Molecular Probes - chemistry Molecular Probes - pharmacology Receptors, Calcitonin - agonists Receptors, Calcitonin - chemistry Receptors, Calcitonin - metabolism Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - chemistry Receptors, G-Protein-Coupled - metabolism Receptors, Gastrointestinal Hormone - agonists Receptors, Gastrointestinal Hormone - chemistry Receptors, Gastrointestinal Hormone - metabolism Receptors, Glucagon - agonists Receptors, Glucagon - metabolism Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology GLP1R CTR GIPR CHO PTH1R cAMP PDB DMEM GHRHR FBS hCT EC50 VPAC1R Allosteric modulation cryo-EM WT Emax GLP-2R sCT GCGR IBMX SCTR PTH2R CRF1R HEK RAMP PEI ND class B1 GPCRs GPCR TM VPAC2R HBSS NAM OVA PAM GLP-1R
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Summary:	[Display omitted] Class B1 G protein-coupled receptors (GPCRs) are peptide hormone receptors and well validated therapeutic targets, however development of non-peptide drugs targeting this class of receptors is challenging. Recently, a series of isoquinoline-based derivates were reported in the patent literature as allosteric ligands for the glucagon receptor subfamily, and two compounds, LSN3451217 and LSN3556672, were used to facilitate structural studies with the glucagon-like peptide-1 receptor (GLP-1R) and glucose dependent insulinotropic peptide receptor (GIPR) bound to orthosteric agonists. Here we pharmacologically characterized stereoisomers of LSN3451217 and LSN3556672, across the class B1 GPCR family. This revealed LSN3556672 isomers are agonists for the glucagon receptor (GCGR), GLP-1R, GIPR and the calcitonin receptor (CTR), albeit the degree of agonism varied at each receptor. In contrast, LSN3451217 isomers were more selective agonists at the GLP-1R, with lower potency at the GCGR and CTR and no activity at the GIPR. All compounds also modulated peptide-mediated cyclic adenosine monophosphate (cAMP) signaling at the GIPR, and to a lesser extent the GLP-1R, in a probe-dependent manner, with modest positive allosteric modulation observed for some peptides, and negligible effects observed with other peptides. In contrast neutral or weak negative/positive allosteric modulation was observed with peptides assessed at the GCGR and CTR. This study expands our knowledge on class B1 GPCR allosteric modulation and may have implications for future structural and drug discovery efforts targeting the class B1 GPCR subfamily.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0006-2952 1873-2968 1873-2968
DOI:	10.1016/j.bcp.2024.116483