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Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2015 Sep 24; Vol. 58 (18), pp. 7526-48. - Publication Year :
- 2015
-
Abstract
- Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.
- Subjects :
- Allosteric Regulation
Animals
Binding, Competitive
Bridged Bicyclo Compounds pharmacokinetics
Bridged Bicyclo Compounds pharmacology
Calcium metabolism
Cyclic AMP metabolism
Dogs
Drug Partial Agonism
Humans
Male
Mice
Models, Molecular
Motor Activity drug effects
Mutagenesis, Site-Directed
Protein Structure, Tertiary
Rats, Sprague-Dawley
Receptors, Metabotropic Glutamate antagonists & inhibitors
Receptors, Metabotropic Glutamate genetics
Receptors, Metabotropic Glutamate metabolism
Stereoisomerism
Triazoles pharmacokinetics
Triazoles pharmacology
Bridged Bicyclo Compounds chemistry
Receptors, Metabotropic Glutamate agonists
Triazoles chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 58
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26313429
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.5b01124