TY - JOUR
T1 - Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery
T2 - Recent Advances with Metabotropic Glutamate Receptors
AU - Lindsley, Craig W.
AU - Emmitte, Kyle A.
AU - Hopkins, Corey R.
AU - Bridges, Thomas M.
AU - Gregory, Karen J.
AU - Niswender, Colleen M.
AU - Conn, P. Jeffrey
PY - 2016/6/8
Y1 - 2016/6/8
N2 - Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1-5 and 7 (mGlu1-5,7) highlighting key concepts ("molecular switches", signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.
AB - Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1-5 and 7 (mGlu1-5,7) highlighting key concepts ("molecular switches", signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.
UR - http://www.scopus.com/inward/record.url?scp=84974602761&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84974602761&partnerID=8YFLogxK
U2 - 10.1021/acs.chemrev.5b00656
DO - 10.1021/acs.chemrev.5b00656
M3 - Review article
C2 - 26882314
AN - SCOPUS:84974602761
VL - 116
SP - 6707
EP - 6741
JO - Chemical Reviews
JF - Chemical Reviews
SN - 0009-2665
IS - 11
ER -