Study of Pharmacology Physiology of N-Methyl-D-Aspartate Receptor Subtypes in theMammalian Central Nervous System

摘要

The goal of this project is to identify pharmacological agents that are specificfor NMDA receptor subtypes for use as anti-nerve gas agents with acceptable side effects. As proposed in the Statement of Work, we have completed the following studies: Task 1. We have determined the potency of 79 drugs at NMDA receptor subtypes using quantitative image analysis of NMDA receptor-radioligand binding autoradiography. Among compounds evaluated (those from the Statement of Work, plus an additional 47 compounds), we have identified several new lead compounds and now have a database for a detailed structure-activity analysis. Task 2 Evaluation of drug potency and selectivity at recombinant NMDA receptors expressed in Xenopus oocytes indicates that differing native NMDA receptor subtypes are due to differing NMDAR2 subunits and that some critical pharmacological properties are not observed in the recombinant receptor system. Channel blocker antagonists displayed two modes of subtype selectivity. Task 3. 3Hhomoquinolinate has been made. As hypothesized, this ligand is specific for one NMDA receptor subtype, and, unexpectedly, also labels a novel site. Task 4. Approximately half of the homoquinolinate, piperazine, and cyclopentane derivatives proposed to be made in the first two years have been made and tested.