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.

Binding site and ligand flexibility revealed by high resolution crystal structures of GluK1 competitive antagonists

“…Crystal structures have not yet been reported for ligands from the extensive series of decahydroisoquinolines which have been developed as glutamate receptor antagonists (Clarke et al, 1997; Ornstein et al, 1996; Ornstein et al, 1992; Weiss et al, 2006). Of this series we chose to study LY466195, one of the most potent GluK1 antagonists reported to date.…”

Effects of the selective kainate receptor antagonist ACET on altered sensorimotor gating in a genetic model of reduced NMDA receptor function

“…administration of ATPA, the tert -butyl analogue of AMPA. In previous studies, ATPA was identified as an AMPA agonist (Ornstein et al, 1996), but was later discovered to be a selective agonist of the GluK1 (formerly GluR5) kainate receptor (Hoo et al, 1999; Jane et al, 2009). In the present study, ATPA (30 mg/kg, i.p.)…”

Glutamate Receptor Ion Channels: Activators and Inhibitors

“…Replacement of the tetrazole with a sulphonyltriazole moiety resulted in an enhancement of potency and selectivity for AMPA receptors (ICso = 0.16 ± 0.79,umol/1 for antagonism of AMPA-mediated depolarizations in the cortical wedge assay) (ORNSTEIN et al 1996b). The activity was found to reside in the (-)- (3 S,4aR,6 S,8aR)-isomer (ICso 0.6,umolll for displacement of [3H]AMPA binding).…”

“…Thus it would appear that the decahydroisoquinoline ring imposes a unique conformation on the molecule. It was observed that for both C-6 epimers it is the compound with the S absolute stereochemistry at C-3 which has the AMPA receptor antagonist activity (ORNSTEIN et al 1996b). This contrasts with observation that for the decahydroisoquinoline series of NMDA receptor antagonists the activity was found to reside in the isomer with R absolute stereochemistry at C-3.…”