dora-22 and Sleep-Initiation-and-Maintenance-Disorders

Insomnia-related sleep disruption can contribute to impaired learning and memory. Treatment of insomnia should ideally improve the sleep profile while minimally affecting mnemonic function, yet many hypnotic drugs (e.g. benzodiazepines) are known to impair memory. Here, we used a rat model of insomnia to determine whether the novel hypnotic drug DORA-22, a dual orexin receptor antagonist, improves mild stress-induced insomnia with minimal effect on memory. Animals were first trained to remember the location of a hidden platform (acquisition) in the Morris Water Maze and then administered DORA-22 (10, 30, or 100 mg/kg doses) or vehicle control. Animals were then subjected to a rodent insomnia model involving two exposures to dirty cages over a 6-hr time period (at time points 0 and 3 hr), followed immediately by a probe trial in which memory of the water maze platform location was evaluated. DORA-22 treatment improved the insomnia-related sleep disruption-wake was attenuated and NREM sleep was normalized. REM sleep amounts were enhanced compared with vehicle treatment for one dose (30 mg/kg). In the first hour of insomnia model exposure, DORA-22 promoted the number and average duration of NREM sleep spindles, which have been previously proposed to play a role in memory consolidation (all doses). Water maze measures revealed probe trial performance improvement for select doses of DORA-22, including increased time spent in the platform quadrant (10 and 30 mg/kg) and time spent in platform location and number of platform crossings (10 mg/kg only). In conclusion, DORA-22 treatment improved insomnia-related sleep disruption and memory consolidation deficits.

Topics: Animals; Pharmaceutical Preparations; Piperidines; Rats; Rodentia; Sleep; Sleep Initiation and Maintenance Disorders; Triazoles

Chronic insomnia is defined as a persistent difficulty with sleep initiation maintenance or non-restorative sleep. The therapeutic standard of care for this condition is treatment with gamma-aminobutyric acid (GABA)

Topics: Acetylcholine; Animals; gamma-Aminobutyric Acid; Hippocampus; Histamine; Hypothalamic Area, Lateral; Male; Orexin Receptor Antagonists; Piperidines; Prefrontal Cortex; Rats; Sleep; Sleep Initiation and Maintenance Disorders; Triazoles; Wakefulness

Topics: Animals; Arousal; Azabicyclo Compounds; Azepines; Benzodiazepines; Cognitive Behavioral Therapy; Doxepin; Dreams; Histamine Agonists; Histamine Antagonists; Humans; Hypnotics and Sedatives; Hypothalamus; Orexin Receptors; Piperazines; Piperidines; Receptors, G-Protein-Coupled; Receptors, GABA; Receptors, Histamine H3; Receptors, Neuropeptide; Sleep Initiation and Maintenance Disorders; Triazoles

Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual orexin 1 and orexin 2 receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional in vivo activity in preclinical sleep models, and has advanced into phase II clinical trials for the treatment of insomnia.

Topics: Animals; Brain; Dogs; Drug Discovery; Humans; Hypnotics and Sedatives; Magnetic Resonance Spectroscopy; Models, Molecular; Orexin Receptors; Piperidines; Protein Binding; Pyridines; Rats; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Sleep; Sleep Initiation and Maintenance Disorders; Stereoisomerism; Structure-Activity Relationship; Triazoles; Wakefulness