The Dopamine D1 Receptor Positive Allosteric Modulator Mevidalen (LY3154207) Enhances Wakefulness in the Humanized D1 Mouse and in Sleep-Deprived Healthy Male Volunteers.

Andrew P Mccarthy,William Kielbasa,Kjell A Svensson,Brian J Eastwood,Claire Brittain,Keith A Wafford,Elaine Shanks,Kevin M Biglan

doi:10.1124/jpet.121.000719

Andrew P Mccarthy, William Kielbasa + Show 6 more

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https://doi.org/10.1124/jpet.121.000719

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Abstract

Dopamine (DA) plays a key role in several central functions including cognition, motor activity, and wakefulness. Although efforts to develop dopamine receptor 1 (D1) agonists have been challenging, a positive allosteric modulator represents an attractive approach with potential better drug-like properties. Our previous study demonstrated an acceptable safety and tolerability profile of the dopamine receptor 1 positive allosteric modulator (D1PAM) mevidalen (LY3154207) in single and multiple ascending dose studies in healthy volunteers (Wilbraham et al., 2021). Herein, we describe the effects of mevidalen on sleep and wakefulness in humanized dopamine receptor 1 (hD1) mice and in sleep-deprived healthy male volunteers. Mevidalen enhanced wakefulness (latency to fall asleep) in the hD1 mouse in a dose dependent [3-100 mg/kg, orally (PO)] fashion when measured during the light (zeitgeber time 5) and predominantly inactive phase. Mevidalen promoted wakefulness in mice after prior sleep deprivation and delayed sleep onset by 5.5- and 15.2-fold compared with vehicle-treated animals, after the 20 and 60 mg/kg PO doses, respectively, when compared with vehicle-treated animals. In humans, mevidalen demonstrated a dose-dependent increase in latency to sleep onset as measured by the multiple sleep latency test and all doses (15, 30, and 75 mg) separated from placebo at the first 2-hour postdose time point with a circadian effect at the 6-hour postdose time point. Sleep wakefulness should be considered a translational biomarker for the dopamine receptor 1 positive allosteric modulator mechanism. SIGNIFICANCE STATEMENT: This is the first translational study describing the effects of a selective dopamine receptor 1 positive allosteric modulator (D1PAM) on sleep and wakefulness in the human dopamine receptor 1 mouse and in sleep-deprived healthy male volunteers. In both species, drug exposure correlated with sleep latency, supporting the use of sleep-wake activity as a translational central biomarker for D1PAM. Wake-promoting effects of D1PAMs may offer therapeutic opportunities in several conditions, including sleep disorders and excessive daytime sleepiness related to neurodegenerative disorders.

Highlights

As an alternative to the D1 receptor agonist approach, we recently discovered a series of D1 positive allosteric modulators (D1PAMs) that could address some of the issues associated with D1 receptor agonists and offer a more physiological approach to activation of D1 receptors with temporal and spatial resolution related to endogenous DA release (Bruns et al, 2018; Hall et al, 2019; Svensson et al, 2019; Svensson et al, 2017)
In the dose-response study in the humanized dopamine D1 mice (hD1) mouse with mevidalen dosed at ZT-5, mevidalen showed a rapid onset of the wake-promoting effects in a dose dependent fashion with a delay to the onset of sleep (Figure 2a-c and Figure 3a)
We recently reported that the selective D1PAMs DETQ and mevidalen produce dose-dependent increases in locomotion in hD1 mice, similar to D1 receptor agonists, but importantly without inducing inverted U-shaped dose responses (Hao et al, 2019; Svensson et al, 2017)

Summary

Introduction

Mevidalen demonstrated a dose-dependent increase in latency to sleep onset as measured by the multiple sleep latency test and all doses (15, 30, 75 mg) separated from placebo at the first 2-hour post dose time point. Development of novel D1 receptor agonists has been challenging due to poor drug-like properties including inverted U-shaped dose-response, tachypylaxis, poor metabolic stability, and tolerability issues. Preclinical studies in transgenic mice expressing the human D1 receptor (hD1 mice) suggest that selective D1PAMs, while sharing many pharmacological properties with D1 receptor agonists, fail to induce inverted U-shaped dose response or rapid tolerance on various behavioral endpoints (Hao et al, 2019; Meltzer et al, 2019; Svensson et al, 2017). When dosed to hD1 mice, D1PAM produce a dose-related increase in forward

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