Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254).
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu5 PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu5 PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift ~ 3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu5 PAMs.
Department of Pharmacology, ‡Vanderbilt Center for Neuroscience Drug Discovery, ¶Center for Structural Biology, and #Vanderbilt Institute for Chemical Biology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Mark
M
Turlington
Meredith J
MJ
Noetzel
Aspen
A
Chun
Ya
Y
Zhou
Rocco D
RD
Gogliotti
Elizabeth D
ED
Nguyen
Karen J
KJ
Gregory
Paige N
PN
Vinson
Jerri M
JM
Rook
Kiran K
KK
Gogi
Zixiu
Z
Xiang
Thomas M
TM
Bridges
J Scott
JS
Daniels
Carrie
C
Jones
Colleen M
CM
Niswender
Jens
J
Meiler
P Jeffrey
PJ
Conn
Craig W
CW
Lindsley
Shaun R
SR
Stauffer
D000114:Acetylene / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000494:Allosteric Regulation / Q000187:drug effects; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010848:Picolinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
C586840:5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide; D000577:Amides; D010848:Picolinic Acids; D064529:Receptor, Metabotropic Glutamate 5; C003142:picolinamide; D000114:Acetylene