Novel indole-2-carboxylates as ligands for the strychnine-insensitive N-methyl-D-aspartate-linked glycine receptor

Abstract

A series of indole-2-carboxylates were prepared and evaluated for their ability to inhibit the binding at the strychnine-insensitive glycine receptor that is associated with the NMDA-PCP-glycine receptor complex. All of the compounds were selective for the glycine site relative to other sites on the receptor macrocomplex and several of the compounds in this series were found to have submicromolar affinity for this receptor. The lead compound, 2-carboxy-6-chloro-3-indoleacetic acid (Ki = 1.6 microM vs [3H]glycine), was also found to noncompetitively inhibit the binding of MK-801, a ligand for the phencyclidine site on the receptor macrocomplex. These latter data suggest that the compound functions as an antagonist at the strychnine-insensitive glycine receptor. The structural activity relationships within this series of indole-2-carboxylates is discussed and several key pharmacophores are identified for this series of glycine ligands. In general, the most potent compounds were the C-3 acetamides, with N-propyl-2-carboxy-6-chloro-3-indoleacetamide having the highest receptor affinity.

One-Pot Synthesis ofcis-Isoquinolonic Acid Derivativesvia Three-Component Reaction of Homophthalic Anhydride with Aldehydes and Amines using Ytterbium(III) Triflate as Catalyst

“…[1] In particular, isoquinolonic acids are useful precursors for the total synthesis of naturally occurring phenanthridine alkaloids [2] such as corynoline, oxocorynoline and epicorynoline as well as indenoisoquinolines [3] possessing significant anti-tumor activity. It is therefore not surprising that many synthetic methods have been developed for these compounds.…”

Ultrasound‐Promoted Reaction of 2‐Chlorobenzoic Acids and Aliphatic Amines

“…of potassium carbonate afforded, after 5 h, the corresponding 2-(alkylamino)benzoic acid with yields superior to those reported in the literature with the use of other preparative procedures. [16][17][18] We also examined the effect of ultrasonic irradiation for the synthesis of these compounds, increasing the yields in a 20 % rate after only 20 min [15] (Scheme 1).…”

“…[16,18,[33][34][35][36] Supporting Information (see footnote on the first page of this article): The experimental and spectroscopic data of 1a-16a and 1b-20b.…”

Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists

“…Tricyclic Quinoxalinediones [28,[30][31][32] In the early 1990s, three structurally distinct antagonists of the NMDA-glycine site were known, including kynurenic acids such as 1 (DCKA) [33][34][35]42,43], indole-2-carboxylic acids such as 2 [36][37][38], and quinoxalinediones such as 3 (DCQX) [39][40][41]. The former two molecules were being extensively modified by several laboratories [44][45][46][47][48][49][50][51][52][53][54][55] at that time and antagonists with high affinity for the glycine site such as 4 (L-689,560) [25] and 5 (MDL 29,951) [56] were synthesized (Chart 1).…”

“…The former two molecules were being extensively modified by several laboratories [44][45][46][47][48][49][50][51][52][53][54][55] at that time and antagonists with high affinity for the glycine site such as 4 (L-689,560) [25] and 5 (MDL 29,951) [56] were synthesized (Chart 1). However, these antagonists unfortunately showed only very weak in vivo activities, as mentioned above.…”