RT Journal Article
SR Electronic
T1 Allosteric Modulation of Endogenous Metabolites as an Avenue for Drug Discovery
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 281
OP 290
DO 10.1124/mol.112.079319
VO 82
IS 2
A1 Wootten, Denise
A1 Savage, Emilia E.
A1 Valant, Celine
A1 May, Lauren T.
A1 Sloop, Kyle W.
A1 Ficorilli, James
A1 Showalter, Aaron D.
A1 Willard, Francis S.
A1 Christopoulos, Arthur
A1 Sexton, Patrick M.
YR 2012
UL http://molpharm.aspetjournals.org/content/82/2/281.abstract
AB G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and a key drug target class. Recently, allosteric drugs that can cobind with and modulate the activity of the endogenous ligand(s) for the receptor have become a major focus of the pharmaceutical and biotechnology industry for the development of novel GPCR therapeutic agents. This class of drugs has distinct properties compared with drugs targeting the endogenous (orthosteric) ligand-binding site that include the ability to sculpt cellular signaling and to respond differently in the presence of discrete orthosteric ligands, a behavior termed “probe dependence.” Here, using cell signaling assays combined with ex vivo and in vivo studies of insulin secretion, we demonstrate that allosteric ligands can cause marked potentiation of previously “inert” metabolic products of neurotransmitters and peptide hormones, a novel consequence of the phenomenon of probe dependence. Indeed, at the muscarinic M2 receptor and glucagon-like peptide 1 (GLP-1) receptor, allosteric potentiation of the metabolites, choline and GLP-1(9–36)NH2, respectively, was ∼100-fold and up to 200-fold greater than that seen with the physiological signaling molecules acetylcholine and GLP-1(7–36)NH2. Modulation of GLP-1(9–36)NH2 was also demonstrated in ex vivo and in vivo assays of insulin secretion. This work opens up new avenues for allosteric drug discovery by directly targeting modulation of metabolites, but it also identifies a behavior that could contribute to unexpected clinical outcomes if interaction of allosteric drugs with metabolites is not part of their preclinical assessment.