1. Synthesis and Pharmacological Characterization of C4 β -Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S,2 S,4 S,5 R,6 S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu 3 Receptor Agonist.
- Author
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Monn JA, Henry SS, Massey SM, Clawson DK, Chen Q, Diseroad BA, Bhardwaj RM, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang XS, Carter JH, Getman BG, Adragni K, Broad LM, Sanger HE, Ursu D, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL, and Hao J
- Subjects
- Animals, Bridged Bicyclo Compounds pharmacokinetics, Crystallography, X-Ray, Cyclic AMP pharmacology, Excitatory Amino Acid Agonists pharmacokinetics, Excitatory Amino Acid Antagonists pharmacology, Humans, Male, Models, Molecular, Molecular Docking Simulation, Molecular Structure, Motor Activity drug effects, Neurons drug effects, Neurons metabolism, Phencyclidine antagonists & inhibitors, Phencyclidine pharmacology, Protein Binding, Rats, Rats, Sprague-Dawley, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds pharmacology, Excitatory Amino Acid Agonists chemical synthesis, Excitatory Amino Acid Agonists pharmacology, Receptors, Metabotropic Glutamate agonists
- Abstract
Multiple therapeutic opportunities have been suggested for compounds capable of selective activation of metabotropic glutamate 3 (mGlu
3 ) receptors, but small molecule tools are lacking. As part of our ongoing efforts to identify potent, selective, and systemically bioavailable agonists for mGlu2 and mGlu3 receptor subtypes, a series of C4β -N-linked variants of (1 S,2 S,5 R,6 S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 1 (LY354740) were prepared and evaluated for both mGlu2 and mGlu3 receptor binding affinity and functional cellular responses. From this investigation we identified (1 S,2 S,4 S,5 R,6 S)-2-amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 8p (LY2794193), a molecule that demonstrates remarkable mGlu3 receptor selectivity. Crystallization of 8p with the amino terminal domain of hmGlu3 revealed critical binding interactions for this ligand with residues adjacent to the glutamate binding site, while pharmacokinetic assessment of 8p combined with its effect in an mGlu2 receptor-dependent behavioral model provides estimates for doses of this compound that would be expected to selectively engage and activate central mGlu3 receptors in vivo.- Published
- 2018
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