STRUCTURE-ACTIVITY STUDIES OF 6-SUBSTITUTED DECAHYDROISOQUINOLINE-3-CARBOXYLIC ACID AMPA RECEPTOR ANTAGONISTS .2. EFFECTS OF DISTAL ACID BIOISOSTERIC SUBSTITUTION, ABSOLUTE STEREOCHEMICAL PREFERENCES, AND IN-VIVO ACTIVITY

We have explored the excitatory amino acid antagonist activity in a se ries of decahydroisoquinoline-3-carboxyic acids, and within this serie s found the potent and selective AMPA antagonist azol-5-yl)ethyl)decah ydroisoquinoline-3-carboxylic acid (1). In this and the preceding pape r, we looked at the structure-activity relationships for AMPA antagoni st activity in this series of compounds. We have already shown that 1 had the optimal stereochemical array and that AMPA antagonist activity was maximized for a two-carbon spacer separating a tetrazole from the bicyclic nucleus. In this paper, we explored the effects of varying t he distal acid and the absolute stereochemical preferences of many of these analogs. We looked at a variety of different acid bioisosteres, including 5-membered hetereocyclic acids such as tetrazole, 1,2,4-tria zole, and 3-isoxazolone; carboxylic, phosphonic, and sulfonic acid; an d acyl sulfonamides. Compounds were evaluated in rat cortical tissue f or their ability to inhibit the binding of radioligands selective for AMPA ([H-3]AMPA), NMDA ([H-3]CGS 19755), and kainic acid ([H-3]kainic acid) receptors and for their ability to inhibit depolarizations induc ed by AMPA (40 mu M), NMDA (40 mu M), and kainic acid (10 mu M). A num ber of compounds from this and the preceding paper were also evaluated in mice for their ability to block maximal electroshock-induced convu lsions and ATPA-induced rigidity in mice.