N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a novel metabotropic glutamate 2 potentiator with potential anxiolytic/antidepressant properties: in vivo profiling suggests a link between behavioral and central nervous system neurochemical changes.
The normalization of excessive glutamatergic neurotransmission through the activation of metabotropic glutamate 2 (mGlu2) receptors may have therapeutic potential in a variety of psychiatric disorders, including anxiety/depression and schizophrenia. Here, we characterize the pharmacological properties of N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a structurally novel, potent, and selective allosteric potentiator of human and rat mGlu2 receptors (EC(50) = 23 and 13 nM, respectively). THIIC produced anxiolytic-like efficacy in the rat stress-induced hyperthermia assay and the mouse stress-induced elevation of cerebellar cGMP and marble-burying assays. THIIC also produced robust activity in three assays that detect antidepressant-like activity, including the mouse forced-swim test, the rat differential reinforcement of low rate 72-s assay, and the rat dominant-submissive test, with a maximal response similar to that of imipramine. Effects of THIIC in the forced-swim test and marble burying were deleted in mGlu2 receptor null mice. Analysis of sleep electroencephalogram (EEG) showed that THIIC had a sleep-promoting profile with increased non-rapid eye movement (REM) and decreased REM sleep. THIIC also decreased the dark phase increase in extracellular histamine in the medial prefrontal cortex and decreased levels of the histamine metabolite tele-methylhistamine (t-MeHA) in rat cerebrospinal fluid. Collectively, these results indicate that the novel mGlu2-positive allosteric modulator THIIC has robust activity in models used to predict anxiolytic/antidepressant efficacy, substantiating, at least with this molecule, differentiation in the biological impact of mGlu2 potentiation versus mGlu2/3 orthosteric agonism. In addition, we provide evidence that sleep EEG and CSF t-MeHA might function as viable biomarker approaches to facilitate the translational development of THIIC and other mGlu2 potentiators.
Fell
Matthew J
MJ
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, DC0510, Indianapolis, IN 46285, USA. fell_matthew@lilly.com
Witkin
Jeffrey M
JM
Falcone
Julie F
JF
Katner
Jason S
JS
Perry
Kenneth W
KW
Hart
John
J
Rorick-Kehn
Linda
L
Overshiner
Carl D
CD
Rasmussen
Kurt
K
Chaney
Stephen F
SF
Benvenga
Mark J
MJ
Li
Xia
X
Marlow
Deanna L
DL
Thompson
Linda K
LK
Luecke
Susan K
SK
Wafford
Keith A
KA
Seidel
Wesley F
WF
Edgar
Dale M
DM
Quets
Anne T
AT
Felder
Christian C
CC
Wang
XuShan
X
Heinz
Beverly A
BA
Nikolayev
Alexander
A
Kuo
Ming-Shang
MS
Mayhugh
Daniel
D
Khilevich
Albert
A
Zhang
Deyi
D
Ebert
Philip J
PJ
Eckstein
James A
JA
Ackermann
Bradley L
BL
Swanson
Steven P
SP
Catlow
John T
JT
Dean
Robert A
RA
Jackson
Kimberley
K
Tauscher-Wisniewski
Sitra
S
Marek
Gerard J
GJ
Schkeryantz
Jeffrey M
JM
Svensson
Kjell A
KA
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001593:Benzyl Compounds / Q000494:pharmacology*; D002460:Cell Line; D002490:Central Nervous System / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D002531:Cerebellum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001593:Benzyl Compounds; D018690:Excitatory Amino Acid Agonists; D007093:Imidazoles; C554953:N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2