Potential Solriamfetol Wake Promotion Mechanisms Shown in Preclinical Trial

The mechanism of solriamfetol, a wake-promoting agent (WPA), may result from norepinephrine and dopamine reuptake inhibition, and hTAAR1 activity may act as an additional mechanism underlying the effects of solriamfetol, according to study results presented at Psych Congress 2022, held from September 17 to 20, 2022, in New Orleans, Louisiana.

Researchers sought to identify solriamfetol activated targets and compare them with WPAs and traditional stimulants. They analyzed in vitro binding and functional studies conducted to measure the activity of comparator WPAs and solriamfetol. The researchers also analyzed locomotor activity studies performed in mice, and electrophysiology studies in slice preparations from mouse ventral tegmental area (VTA).

In vitro studies showed agonist activity of solriamfetol at mouse, human, and rat TAAR1 receptors. The researchers noted hTAAR1 EC50 values overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro, within the clinically observed therapeutic plasma concentration range. There was no TAAR1 agonist activity in either the DAT/NET inhibitor bupropion or modafinil.

The firing frequency of dopaminergic VTA neurons in mouse brain slices were observed to be dose-dependently inhibited by solriamfetol, similar to known TAAR1 agonists. Locomotor activity in naive mice was not increased by solriamfetol, which inhibited locomotor activity in DAT knockout mice.

Researchers conclude, “Preclinical studies have identified agonist activity at the TAAR1 receptor and lower potency agonist activity at 5-HT_1A receptors for solriamfetol, in addition to its activity as a DAT/NET inhibitor.” They add, “TAAR1 agonists are modulators of monoamine transmission with potential wake-promoting effects seen in preclinical studies,” which suggests hTAAR1 activity may be an additional mechanism of solriamfetol.

Disclosure: This research was supported by Axsome Therapeutics, Jazz Pharmaceuticals. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.