title: 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.
abstract: We have explored the excitatory amino acid antagonist activity in a series of decahydroiso-quinoline-3-carboxyic acids, and within this series found the potent and selective AMPA antagonist (3SR,4aRS,6RS,8aRS)-6-(2-(1H-tetrazol-5-yl )ethyl) decahydroisoquinoline-3-carboxylic acid (1). In this and the preceding paper, we looked at the structure-activity relationships for AMPA antagonist 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 the 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-triazole, and 3-isoxazolone; carboxylic,phosphonic, and sulfonic acid; and acyl sulfonamides. Compounds were evaluated in rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM), and kainic acid (10 microM). A number of compounds from this and the preceding paper were also evaluated in mice for their ability to block maximal electroshock-induced convulsions and ATPA-induced rigidity in mice.
authors.affiliation: Lilly Research Laboratories, Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Ornstein
authors.forename: M B
authors.initials: MB
authors.lastname: Arnold
authors.forename: N K
authors.initials: NK
authors.lastname: Allen
authors.forename: T
authors.initials: T
authors.lastname: Bleisch
authors.forename: P S
authors.initials: PS
authors.lastname: Borromeo
authors.forename: C W
authors.initials: CW
authors.lastname: Lugar
authors.forename: J D
authors.initials: JD
authors.lastname: Leander
authors.forename: D
authors.initials: D
authors.lastname: Lodge
authors.forename: D D
authors.initials: DD
authors.lastname: Schoepp
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D004597:Electroshock; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007608:Kainic Acid / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010875:Pipecolic Acids / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012640:Seizures / Q000517:prevention & control*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
chemical_list: D002264:Carboxylic Acids; D007546:Isoquinolines; D010875:Pipecolic Acids; D018091:Receptors, AMPA; C053672:selfotel; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid