E1R

Pharmacology

E1R is a Sigma-1 (σ1) PAM derivative of Phenylpiracetam. It is one of the only Sigma-1 (σ1) PAMs without Agonist affinity, meaning it has a superior effect profile [1].

Methylphenylpiracetam (E1R) was discovered to target only the Sigma-1 (σ1) site in in vitro pharmacological profiling assays. E1R has been shown to alleviate scopolamine-induced cognitive impairment in mice, as assessed using passive avoidance and spontaneous alternation tests. The effects of E1R were antagonized by the selective Sigma-1 (σ1) antagonist NE-100, suggesting a Sigma-1 (σ1) PAM effect in vivo [1].

The stereochemistry of allosteric Sigma-1 (σ1) modulators is an important factor in their activity. For example, E1R is a 4R,5S-isomer of methylphenylpiracetam, and it has been shown to be a selective PAM of Sigma-1 (σ1) . However, its 4S,5R-isomer, called UN101063, has no Sigma-1 (σ1) activity. Therefore, the stereochemistry of Sigma-1 (σ1) PAMs needs to be carefully considered in the design and optimization of novel compounds [1].

E1R, being based on phenylpiracetam, has a high predicted ADMET safety profile and a low predicted dose. A key advantage of E1R over other Sigma-1 (σ1) receptor modulators is its lack of effects on locomotor activity. Therefore, E1R represents a promising lead compound for further development as a therapeutic agent, particularly for treating symptoms of cognitive disorders and neurodegenerative diseases. The only problem with E1R is of its difficulty to produce due to its stereoisomer configuration.

E1R only slightly increased locomotor activity, compared with Sigma-1 agonists which significantly increase locomotor activity in comparison.

Safety is untested, however due to it's structural similarities with Piracetam and also predicted safety (via ADMETLabs), it likely is tolerable.

Half life is unknown. Estimated human dose 3-5mg IN.