Novel bicyclo[3.1.0]hexane analogs as antagonists of metabotropic glutamate 2/3 receptors for the treatment of depression.
Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.0]hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2IC5046±14.2nM, hmGlu3IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3receptors both in vitro and in vivo.
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA. Electronic address: DRESSMAN_BRUCE_A@lilly.com.
Bruce A
BA
Dressman
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Eric G
EG
Tromiczak
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Mark D
MD
Chappell
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Allie E
AE
Tripp
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Steven J
SJ
Quimby
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Tatiana
T
Vetman
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Adam M
AM
Fivush
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
James
J
Matt
Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain.
Carlos
C
Jaramillo
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Renhua
R
Li
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Albert
A
Khilevich
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Maria-Jesus
MJ
Blanco
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Stephon C
SC
Smith
Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain.
Mercedes
M
Carpintero
Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain.
José Eugenio
JE
de Diego
Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain.
Mario
M
Barberis
Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain.
Susana
S
García-Cerrada
Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain.
José F
JF
Soriano
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Jeffrey M
JM
Schkeryantz
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Jeffrey M
JM
Witkin
Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK.
Keith A
KA
Wafford
Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK.
Wesley
W
Seidel
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Thomas
T
Britton
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Carl D
CD
Overshiner
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Xia
X
Li
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Xu-Shan
XS
Wang
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Beverly A
BA
Heinz
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
John T
JT
Catlow
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Steven
S
Swanson
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
David
D
Bedwell
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Paul L
PL
Ornstein
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA.
Charles H
CH
Mitch
D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D004285:Dogs; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000882:Haplorhini; D006586:Hexanes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000928:Antidepressive Agents; D001643:Bridged Bicyclo Compounds; D006586:Hexanes; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid
Antidepressant; Major depressive disorders; Metabotropic glutamate; mGlu(2/3) antagonist