Abstract Details

Title Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion

Topic Sleep

Presentation(s) P4 - Poster Session 4 (8:00 AM-9:00 AM)

Poster/Presentation
Number 11-005

Objective Preclinical pharmacology studies were conducted to identify new targets activated by solriamfetol and compare them to those of wake-promoting agents (WPAs) and traditional stimulants.

Background Solriamfetol is a 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, but other mediators of cognition and arousal warrant exploration. Preclinical studies in rodents and non-human primates indicate that TAAR1 agonists may have wake promoting properties.

Design/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. Solriamfetol also exhibited agonist activity at serotonin 1A (5HT_1A) receptor in vitro, with lower potency (EC₅₀=25µM). 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-HT_1A 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 TAAR1 activity may represent an additional mechanism underlying the effects of solriamfetol.

Authors/Disclosures
Gregory S. Parks, PhD (Axsome Therapeutics) PRESENTER	Dr. Parks has received personal compensation for serving as an employee of Axsome Therapeutics. Dr. Parks has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Dr. Parks has stock in Axsome Therapeutics. Dr. Parks has stock in Jazz Pharmaceuticals.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Wayne Macfadden, MD, PT	Dr. Macfadden has received personal compensation for serving as an employee of Jazz pharma. Dr. Macfadden has stock in Jazz pharma.
Craig Chepke (Excel Psychiatric Associates)	Craig Chepke has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Janssen. Craig Chepke has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Otsuka. Craig Chepke has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine. Craig Chepke has received personal compensation in the range of $100,000-$499,999 for serving on a Speakers Bureau for Neurocrine. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for AbbVie. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Acadia. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Otsuka. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Takeda. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Janssen. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Ironshore. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Teva. Craig Chepke has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sunovion. Craig Chepke has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Intracellular. Craig Chepke has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Eisai. Craig Chepke has received research support from Acadia. Craig Chepke has received research support from Harmony. Craig Chepke has received research support from Neurocrine.

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