Positive and negative modulation of group I metabotropic glutamate receptors.
A discriminating pharmacophore model for noncompetitive metabotropic glutamate receptor antagonists of subtype 1 (mGluR1) was developed that facilitated the discovery of moderately active mGluR1 antagonists. One scaffold was selected for the design of several focused libraries where different substitution patterns were introduced. This approach facilitated the discovery of potent mGluR1 antagonists, as well as positive and negative mGluR5 modulators, because both receptor subtypes share similar binding pockets. For mGluR1 antagonists, a homology model of the mGlu1 receptor was established, and a putative binding mode within the receptor's transmembrane domain was visualized.
Vanejevs
Maksims
M
Institute of Organic Synthesis, Riga, Latvia.
Jatzke
Claudia
C
Renner
Steffen
S
Müller
Sibylle
S
Hechenberger
Mirko
M
Bauer
Tanja
T
Klochkova
Anna
A
Pyatkin
Ilya
I
Kazyulkin
Denis
D
Aksenova
Elena
E
Shulepin
Sergey
S
Timonina
Olga
O
Haasis
Ariane
A
Gutcaits
Aleksandrs
A
Parsons
Christopher G
CG
Kauss
Valerjans
V
Weil
Tanja
T
D000114:Acetylene / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D006224:Cricetinae; D003412:Cricetulus; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007295:Inositol Phosphates / Q000096:biosynthesis; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013329:Structure-Activity Relationship
D001381:Azepines; D003517:Cyclopentanes; D018683:Excitatory Amino Acid Agents; D007295:Inositol Phosphates; D009570:Nitriles; D010879:Piperazines; D011804:Quinolines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D000114:Acetylene; D002118:Calcium