Selective antagonists at group I metabotropic glutamate receptors: synthesis and molecular pharmacology of 4-aryl-3-isoxazolol amino acids

Hasse Kromann; Frank A Sløk; Tine B Stensbøl; Hans Bräuner-Osborne; Ulf Madsen; Povl Krogsgaard-Larsen

doi:10.1021/jm010443t

Selective antagonists at group I metabotropic glutamate receptors: synthesis and molecular pharmacology of 4-aryl-3-isoxazolol amino acids

J Med Chem. 2002 Feb 14;45(4):988-91. doi: 10.1021/jm010443t.

Authors

Hasse Kromann¹, Frank A Sløk, Tine B Stensbøl, Hans Bräuner-Osborne, Ulf Madsen, Povl Krogsgaard-Larsen

Affiliation

¹ NeuroScience PharmaBiotec Research Center, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.

PMID: 11831912
DOI: 10.1021/jm010443t

Abstract

Homologation of (S)-glutamic acid (Glu, 1) and Glu analogues has previously provided ligands with activity at metabotropic Glu receptors (mGluRs). The homologue of ibotenic acid (7), 2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid (HIBO, 8), and the 4-phenyl derivative of 8, compound 9a, are both antagonists at group I mGluRs. Here we report the synthesis and molecular pharmacology of HIBO analogues 9b-h containing different 4-aryl substituents. All of these compounds possess antagonist activity at group I mGluRs but are inactive at group II and III mGluRs.

MeSH terms

Animals
Brain / physiology
CHO Cells
Cricetinae
Cyclic AMP / biosynthesis
Electrophysiology
Excitatory Amino Acid Antagonists / chemical synthesis*
Excitatory Amino Acid Antagonists / chemistry
Excitatory Amino Acid Antagonists / pharmacology
Hydrolysis
In Vitro Techniques
Isoxazoles / chemical synthesis*
Isoxazoles / chemistry
Isoxazoles / pharmacology
Phosphatidylinositols / metabolism
Radioligand Assay
Rats
Receptors, Metabotropic Glutamate / drug effects*
Structure-Activity Relationship

Substances

Excitatory Amino Acid Antagonists
Isoxazoles
Phosphatidylinositols
Receptors, Metabotropic Glutamate
Cyclic AMP