Discovery of orally efficacious tetracyclic metabotropic glutamate receptor 1 (mGluR1) antagonists for the treatment of chronic pain.
Metabotropic glutamate receptor 1 (mGluR1) plays important roles in the neurotransmission and pathogenesis of several neurological disorders, including chronic pain. Antagonists of mGlur1 are suggested to be useful for the treatment of pain. Herein, we report the discovery of a novel series of tetracyclic mGluR1 antagonists, such as 23c and 23e, with oral efficacy of ED50 of 8 and 5.1 mg/kg, respectively, in rat spinal nerve ligation neuropathic pain model.
Wu
Wen-Lian
WL
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. wen-lian.wu@spcorp.com
Burnett
Duane A
DA
Domalski
Martin
M
Greenlee
William J
WJ
Li
Cheng
C
Bertorelli
Rosalia
R
Fredduzzi
Silva
S
Lozza
Gianluca
G
Veltri
Alessio
A
Reggiani
Angelo
A
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D002908:Chronic Disease; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000700:Analgesics; D006576:Heterocyclic Compounds, 4 or More Rings; D007191:Indazoles; D009025:Morpholines; D011725:Pyridines; D011758:Pyrroles; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1