Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion

Abstract: Introduction: Solriamfetol is a wake-promoting agent (WPA) approved for the treatment of excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea. The wake-promoting mechanism of solriamfetol may result from dopamine and norepinephrine reuptake inhibition. Preclinical pharmacology studies were conducted to identify additional targets activated by solriamfetol and compare them to that of WPAs and traditional stimulants. Methods: In vitro binding and functional studies were conducted to measure the activity of solriamfetol and comparator WPAs. Electrophysiology studies were conducted in slice preparations from mouse ventral tegmental area (VTA). Locomotor activity studies were conducted in mice. Results: In vitro studies showed agonist activity of solriamfetol at human, mouse, and rat TAAR1 receptors. hTAAR1 EC50 values (10–16 µM) were within the clinically observed therapeutic plasma concentration range and overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro. Neither modafinil nor the DAT/NET inhibitor bupropion had TAAR1 agonist activity. Solriamfetol (1–10 µM) dose-dependently inhibited the firing frequency of dopaminergic VTA neurons in mouse brain slices, similar to known TAAR1 agonists. Unlike traditional stimulants, solriamfetol did not increase locomotor activity in naive mice, but inhibited locomotor activity in DAT knockout mice. Conclusions: Preclinical studies have identified agonist activity at the TAAR1 receptor and lower potency agonist activity at 5-HT1A receptors for solriamfetol, in addition to its activity as a DAT/NET inhibitor. TAAR1 agonists are modulators of monoamine transmission with potential wake-promoting effects seen in preclinical studies, so hTAAR1 activity may represent an additional mechanism underlying the effects of solriamfetol.Short Description: Solriamfetol is a wake-promoting agent (WPA) approved for the treatment of excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea. The mechanism of solriamfetol may result from dopamine and norepinephrine reuptake inhibition. Preclinical pharmacology studies were conducted to identify additional targets activated by solriamfetol. Agonist activity at the TAAR1 receptor and lower potency agonist activity at 5-HT1A receptors for solriamfetol was identified. hTAAR1 activity may represent an additional mechanism underlying the effects of solriamfetol.Name of Sponsoring Organization(s): Axsome Therapeutics, Jazz Pharmaceuticals