The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors.
OBJECTIVE
Here, 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.


METHODS
E1R was tested for sigma receptor binding activity in a [³H](+)-pentazocine assay, in bradykinin (BK)-induced intracellular Ca²⁺ concentration ([Ca²⁺](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.


RESULTS
Pretreatment 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 [Ca²⁺](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.


CONCLUSIONS
E1R 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.
Latvian Institute of Organic Synthesis, Riga, Latvia.
L
L
Zvejniece
E
E
Vavers
B
B
Svalbe
R
R
Vilskersts
I
I
Domracheva
M
M
Vorona
G
G
Veinberg
I
I
Misane
I
I
Stonans
I
I
Kalvinsh
M
M
Dambrova
D000081:Acetamides / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000494:Allosteric Regulation; D000647:Amnesia / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004357:Drug Synergism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D018697:Nootropic Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010889:Piracetam / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism; D000097605:Sigma-1 Receptor
D000081:Acetamides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D010889:Piracetam; D011760:Pyrrolidinones; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C000592155:2-(5-methyl-2-oxo-4-phenylpyrrolidin-1-yl)acetamide
CNS drugs; E1R; behaviour; cognition; neurodegenerative diseases; racetam; receptor binding; scopolamine; sigma-1 receptor