Substituted Analogues of GV150526 as Potent Glycine Binding Site Antagonists in Animal Models of Cerebral Ischemia

Abstract

A series of analogues of the indole-2-carboxylate GV150526, currently in clinical trials as a potential neuroprotective agent for the control of the cerebral damage after stroke onset, was designed based on previous studies dealing with the electronic features of the north-east region of the glycine binding site associated with the NMDA receptor. In particular, the substitution of the para position of the terminal phenyl ring of GV150526 with suitable hydrophilic groups resulted in the identification of a new class of glycine antagonists. These compounds exhibited nanomolar in vitro affinity to the glycine binding site, high receptor selectivity, and outstanding in vivo potency. In particular, 3-[(E)-2-[(4-ureidomethylphenyl)aminocarbonyl]ethenyl]-4, 6-dichloroindole-2-carboxylic acid was found to be highly effective in the middle cerebral artery occlusion (MCAo) model in the rat, an animal model of focal ischemia, when given both prior to and after the occlusion of the middle cerebral artery. Notably, a significant neuroprotective effect was seen in this model postischaemia, when the administration of this compound was delayed up to 6 h from the occlusion of the middle cerebral artery, further confirming the wide therapeutic window seen for GV150526A.

Synthesis of some urea and thiourea derivatives of naphtha[1,2-d]thiazol-2-amine as anti-Parkinsonian agents that cause neuroprotection against haloperidol-induced oxidative stress in mice

“…The urea functionality is a key structural element of many biologically active compounds including neuroprotectants (Di Fabio et al, 1999;Choi et al, 2007). Furthermore, a series of urea substituted benzothiazoles are said to be effective in controlling or prevention of PD (Flohr et al, 2003(Flohr et al, , 2004.…”

Neuroprotective effect of STAZN, a novel azulenyl nitrone antioxidant, in focal cerebral ischemia in rats: Dose–response and therapeutic window

“…In rats whose STAZN treatment was begun at 2 or 3 hours after onset of MCAo, neurological behavior improved significantly and was associated with 58.6% and 42.2% reductions of cortical and total infarct size, respectively, relative to vehicletreated controls. The width the therapeutic window of STAZN is similar to that of other neuroprotectants, although other studies often employed a shorter duration of ischemia (Di Fabio, Conti et al 1999;Yrjanheikki, Tikka et al 1999;Piao, Kim et al 2003;Yu, Kim et al 2005;Xu, Croslan et al 2006). Relatively few therapeutics, such as albumin, have shown efficacy when administered more than 3 hours after the onset of a 2-hour ischemic insult (Belayev, Liu et al 2001;Mary, Wahl et al 2001;Williams, Berti et al 2004).…”

Antagonists of AMPA/KA and NMDA (glycine site) glutamate receptors

“…administration) as gavestinel, which also had strong analgesic properties [3,7,37]. An active antagonist was also produced by introduction of a urea moiety into the "bridge" between C3 and the benzene ring (structure XXIf).…”