The cognition‐enhancing activity of E1R, a novel positive allosteric modulator of sigma‐1 receptors

Abstract

BACKGROUND AND PURPOSEHere, we describe the in vitro and in vivo effects of (4R,5S)-2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide (E1R), a novel positive allosteric modulator of sigma-1 receptors. EXPERIMENTAL APPROACHE1R was tested for sigma receptor binding activity in a ]i) assays and in an electrically stimulated rat vas deferens model. E1R's effects on cognitive function were tested using passive avoidance (PA) and Y-maze tests in mice. A selective sigma-1 receptor antagonist (NE-100), was used to study the involvement of the sigma-1 receptor in the effects of E1R. The open-field test was used to detect the effects of E1R on locomotion. KEY RESULTSPretreatment with E1R enhanced the selective sigma-1 receptor agonist PRE-084's stimulating effect during a model study employing electrically stimulated rat vasa deferentia and an assay measuring the BK-induced [Ca 2+ ]i increase. Pretreatment with E1R facilitated PA retention in a dose-related manner. Furthermore, E1R alleviated the scopolamine-induced cognitive impairment during the PA and Y-maze tests in mice. The in vivo and in vitro effects of E1R were blocked by treatment with the selective sigma-1 receptor antagonist NE-100. E1R did not affect locomotor activity. CONCLUSION AND IMPLICATIONSE1R is a novel 4,5-disubstituted derivative of piracetam that enhances cognition and demonstrates efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects are attributed to its positive modulatory action on the sigma-1 receptor and this activity may be relevant when developing new drugs for treating cognitive symptoms related to neurodegenerative diseases. AbbreviationsBK, bradykinin; [Ca 2+ ]i, intracellular calcium ion concentration; E1R, (4R,5S)-

The activity of selective sigma-1 receptor ligands in seizure models in vivo

“…Previously we showed that E1R, a phenylpiracetam derivative, is selective positive allosteric Sig1R modulator [18,38]. In this study E1R showed anti-convulsive effects both in PTZ-and BIC-induced seizure models.…”

“…This allows us to confirm the anti-convulsive properties of positive allosteric Sig1R modulators and the role of Sig1R in the mode of action of these compounds. Among all positive allosteric Sig1R modulators, E1R is the only one known modulator that possesses memory-improving effects [18]. Phenytoin treatment on epilepsy has been shown to induce learning and memory deficit.…”

“…NE-100 has demonstrated anti-allodynic activity in capsaicin-induced mechanical hypersensitivity model [17]. In addition, a recently discovered Sig1R positive allosteric modulator E1R enhanced cognition and demonstrated efficacy against scopolamine-induced cholinergic dysfunction in mice [18]. It has been shown that E1R enhances the activity of PRE-084, while NE-100 blocks the in vivo effects of E1R [18].…”

“…In addition, a recently discovered Sig1R positive allosteric modulator E1R enhanced cognition and demonstrated efficacy against scopolamine-induced cholinergic dysfunction in mice [18]. It has been shown that E1R enhances the activity of PRE-084, while NE-100 blocks the in vivo effects of E1R [18]. Thus far the comparative anti-convulsive effects and interactions of Sig1R ligands have not been studied in the same experimental settings.…”

Recent Advances in the Realm of Allosteric Modulators for Opioid Receptors for Future Therapeutics

“…E1R augmented the binding of [ 3 H]ditolylguanidine, a nonselective sigma receptor radioligand, but was not able to show any allosteric effect on sigma-1 receptors using [ 3 H](+)-pentazocine, a sigma-1 receptor agonist 70 (Figure 8). E1R did not increase contractions in the vas deferens assay when co-administered with PB-28, a sigma-2 receptor agonist, but did potentiate the effect of PRE-084 upon bradykinin-induced intracellular Ca 2+ increase in vitro.…”