The sigma-1 receptor (σ1R， S1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. Moreover, the σ1R also is a transmembrane protein expressed in many different tissue types, and particularly concentrated in certain regions of the central nervous system. Hence, σ1R has been implicated in several phenomena, including neurodegenerative disease, cardiovascular function, schizophrenia, clinical depression, the effects of cocaine abuse, and cancer. This also shows that σ1R is a potential target for various diseases. Therefore, we will introduce a selective σ1 receptor agonist, named PRE-084.

PRE-084 is a highly selective σ1 receptor (S1R) agonist, with an IC₅₀ of 44 nM.

Firstly, PRE-084 (0.1-100 µM; 24 h) protects cultured cortical neurons against β-amyloid toxicity (maximally neuroprotective at 10 µM) and reduces the levels of proapoptotic protein Bax at 10 µM. In other words, PRE-084 might function as a neuroprotectant agent in Alzheimer’s disease.

Moreover, research shows that PRE-084-mediated neuroprotection involves increased neurotrophic support, reduction of reactive astrogliosis and possibly enhancement of a microglial/macrophage phenotype involved in tissue repair and functional restoration.

In addition, PRE-084 (0.25 mg/kg; i.p.; 3 times a week for 8 weeks) displays beneficial effects on motor performance (improves motor neuron survival, ameliorates paw abnormality and grip strength performance) in wobbler mice. At the same time, PRE-084 shows neuroprotective effects (increases the levels of BDNF in the gray matter). Moreover, PRE-084 (1 mg/kg; i.p.; single) protects the heart by activating the Akt‑eNOS pathway in myocardial infarction model.

In conclusion, PRE-084 is a promising σ1 receptor agonist for the research of σ1 receptor-related diseases.

Reference:

[1] Marrazzo A, et al. Neuroreport. 2005 Aug 1;16(11):1223-6.

[2] Peviani M, et al. Neurobiol Dis. 2014 Feb;62:218-32.

[3] Gao QJ, et al. Chin Med J (Engl). 2018 Mar 5;131(5):539-543.

[4] Merlos M, et al. Handb Exp Pharmacol. 2017;244:131-161.