Synthesis and Pharmacological Characterization of N³-Substituted Willardiine Derivatives:  Role of the Substituent at the 5-Position of the Uracil Ring in the Development of Highly Potent and Selective GLU_K5 Kainate Receptor Antagonists

Abstract

Some N3-substituted analogues of willardiine such as 11 and 13 are selective kainate receptor antagonists. In an attempt to improve the potency and selectivity for kainate receptors, a range of analogues of 11 and 13 were synthesized with 5-substituents on the uracil ring. An X-ray crystal structure of the 5-methyl analogue of 13 bound to GLUK5 revealed that there was allowed volume around the 4- and 5-positions of the thiophene ring, and therefore the 4,5-dibromo and 5-phenyl (67) analogues were synthesized. Compound 67 (ACET) demonstrated low nanomolar antagonist potency on native and recombinant GLUK5-containing kainate receptors (KB values of 7 +/- 1 and 5 +/- 1 nM for antagonism of recombinant human GLUK5 and GLUK5/GLUK2, respectively) but displayed IC50 values >100 microM for antagonism of GLUA2, GLUK6, or GLUK6/GLUK2.

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…LY382884 is a competitive antagonist of heteromeric kainate receptors, including GluK1/ GluK2 and GluK1/GluK5, with similar potencies as at homomeric GluK1 (Bortolotto et al, 1999;Alt et al, 2004). The willardiine analogs UBP302 (More et al, 2004), (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)-5-methylpyrimidine-2,4-dione (UBP310) (Mayer et al, 2006), and (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione (Dolman et al, 2007;Dargan et al, 2009) also are selective for 2,4-Epi-neoDH, 2,4-epi-neodysiherbaine; ACET, (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione; CNQX, 6-cyano-7-nitroquinoxaline-2, 3-dione;LU115455, N-(1-(1-carboxymethyl-5,6,7,8-tetrahydro-benzo͓f͔quinoxaline-2,3-(1H,4H) 6,7,methyl-urea; LU97175, 1-benzamido-7-pyrrol-1-yl-6-trifluoromethylquinoxaline-2,3-(1H,4H)-dione; LY377770, (3S,4aR,6S,8aR)-6-(((1H-tetrazol-5-ylmethyl)oxy)methyl)-1,2, 3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid; N.E., no effect; NS102, 5-nitro-6,7,8,9-tetrahydrobenzo͓g͔indole-2,3-dione-3-oxime; UBP296, (R,S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl)pyrimidine-2,4-dione; UBP302, 1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl)pyrimidine-2,4-dione; UBP304, 1-(2-amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione. K i values are for displacing ͓3H͔AMPA binding to BHK cells stably transfected with GluK2 (Tygesen et al, 1995).…”

Novel Analogs and Stereoisomers of the Marine Toxin Neodysiherbaine with Specificity for Kainate Receptors

“…Furthermore, no compounds exist that broadly inhibit KARs (of all stoichiometries) without also antagonizing AMPARs (Kew and Kemp, 2005). For example, substitution at the 5-position of the uracil ring of N 3 -substituted willardiine derivatives generates potent and selective GluR5 KAR antagonists (Dolman et al, 2007). Noncompetitive antagonists also exist for GluR5-containing receptors (Valgeirsson et al, 2003;Christensen et al, 2004;Valgeirsson et al, 2004).…”

PSD-95 regulates synaptic kainate receptors at mouse hippocampal mossy fiber-CA3 synapses

“…ACET (UBP316, Dolman et al, 2007), D-AP5 and DCG-IV were purchased from Tocris Bioscience (Bristol, UK). Tetrodotoxin was purchased from Funakoshi (Tokyo, Japan).…”