Methyl Substitution of 2-Aminobicyclo[3.1.0]hexane 2,6-Dicarboxylate (LY354740) Determines Functional Activity at Metabotropic Glutamate Receptors:  Identification of a Subtype Selective mGlu2 Receptor Agonist

• Published in: Journal of medicinal chemistry 2005-05, Vol.48 (10), p.3605-3612
• Main Authors: Dominguez, Carmen, Prieto, Lourdes, Valli, Matthew J, Massey, Steven M, Bures, Mark, Wright, Rebecca A, Johnson, Bryan G, Andis, Sherri L, Kingston, Ann, Schoepp, Darryle D, Monn, James A
• Format: Article
• Language: English
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - pharmacology; Cell Line; Cricetinae; Cyclic AMP - biosynthesis; Glutamatergic system (aspartate and other excitatory aminoacids); Humans; In Vitro Techniques; Medical sciences; Models, Molecular; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Radioligand Assay; Rats; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - physiology; Recombinant Proteins - agonists; Recombinant Proteins - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040222y

LY354740 (1) is a highly potent and selective agonist of metabotropic glutamate (mGlu) receptors 2 and 3. In the present study, we have prepared C3- and C4-methyl-substituted variants of rac-1, compounds 5, 9, and 13. Each of these racemic methyl-substituted analogues displaced specific binding of the mGlu2/3 receptor antagonist 3H-2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (3H-LY341495) from membranes expressing mGlu2 or mGlu3 receptor subtypes. Evaluation of the functional effects of this series on second messenger responses in cells expressing human mGlu2 or mGlu3 receptors revealed C3β-methyl analogue 5 to possess antagonist properties at both mGlu2 and mGlu3 receptors while C4β-methyl analogue 9 acts as a full agonist at each of these targets. Unexpectedly, we found that incorporation of a methyl substituent at the C4α-position as in analogue 13 results in a mixed mGlu2 agonist/mGlu3 antagonist pharmacological profile. All of the mGlu2 agonist and mGlu3 antagonist activity of rac-13 was found to reside in its resolved (+)-isomer.