Bicyclic Metabotropic Glutamate Receptor Ligands

Categories: “Neurodegenerative Therapeutics“

Reference #: 1998-033

OTC Contact: Ruchika Nijhara, Ph.D. (Directory Information | Send a Message)

Description

Glutamate receptors play a role in numerous neurological, neurodegenerative, psychiatric and psychological disease states. New derivatives of the glutamate agonist, (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S, 3R)-ACPD], have been synthesized and screened for potency and biological activity. Biological data supports the activity of these compounds for a variety of mGluRs. In-vitro studies reveal that a specific novel bicyclic compound, ABHxD-I, is between 6 to 34-fold more potent in EC50 assays for mGluRs than (1S, 3R)-ACPD. These compounds demonstrate potential as therapeutic agents in pharmaceutical compositions and can be used in research to probe mGluR function.

Applications

• Novel ligands for mGluRs with potential therapeutic application
• Methods of using such ligands for the treatment of neuronal degeneration, stroke and Alzheimer’s disease

Advantages

• Compounds of the invention demonstrate significantly higher potency for mGluRs than (1S, 3R)-ACPD.

Stage of Development

• In-vitro studies validating the potency and activity of compounds of the invention

Relevant Publications

Tuckmantel, W.; Kozikowski, A. P.; Wang, S.; Pshenichkin, S.; Wroblewski, J. T. Synthesis, molecular modelling, and biology of the 1-benzyl derivative of APDC – an apparent mGluR6 selective ligand. Bioorg. Med. Chem. Lett. 1997, 7, 601-606.

Kozikowski, A. P.; Araldi, G. L.; Tuckmantel, W.; Pshenichkin, S.; Surina, E.; Wroblewski, J. T. 1-Amino-APDC, a partial agonist of group II metabotropic glutamate receptors with neuroprotective properties. Bioorg. Med. Chem. Lett. 1999, 9, 1721-1726.

Kozikowski, A. P.; Steensma, D.; Araldi, G. L.; Tuckmantel, W.;Wang, S.; Pshenichkin, S.; Surina, E.; Wroblewski, J. T. Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I, a potent mGluR agonist. J. Med. Chem. 1998, 41, 1641-1650.

Kozikowski, A. P.; Araldi, G. L.; Flippen-Anderson, J.; George, C.; Pshenichkin, S.; Surina, E.; Wroblewski, J. Synthesis and metabotropic glutamate receptor activity of a 2-aminobicyclo-[3.2.0]heptane-2,5-dicarboxylic acid, a molecule possessing an extended glutamate conformation. Bioorg. Med. Chem. Lett. 1998, 8, 925-930.

Ma, D.; Tian, H.; Sun, H.; Kozikowski, A. P.; Pshenichkin, S.; Wroblewski, J. T. Synthesis and biological activity of cyclic analogues of MPPG and MCPG as metabotropic glutamate receptor antagonists. Bioorg. Med. Chem. Lett. 1997, 7, 1195-1198.

Kozikowski, A. P.; Steensma, D.; Varasi, M.; Pshenichkin, S.;Surina, E.; Wroblewski, J. T. Alpha-substituted quisqualic acid analogues: new metabotropic glutamate receptor group II selective antagonists. Bioorg. Med. Chem. Lett. 1998, 8, 447-452.

INVENTORS

Alan P. Kozikowski, et al.

Patent Status

U.S. Patent Nos. 6,204,292; 6,376,532; and 6,825,211; Priority: November 5, 1997