Discovery of Selective MT1 Melatonin Receptor Ligands for Sleep Disorders

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DESCRIPTION (provided by applicant): Sleep disorders due to stress, illness, chronic pain, and poor sleep habits are a major social and health concern, resulting in lost work, decreased attention and productivity, daytime drowsiness, incoordination, and often leading to serious accidents. At present, these sleep disorders are treated by over-the-counter or prescription hypnotic medications. Some of these medications, however, show prominent side effects, including sedation, memory problems, headaches, discontinuation insomnia, and sleepwalking, and may also become habit forming. Melatonin, a neurohormone secreted in a circadian fashion by the pineal gland, promotes sleep and regulates circadian rhythmicity by activating two membrane-bound G-protein coupled receptors in humans: the MT1 and MT2. Melatonin receptor agonists represent a new class of drugs indicated for the treatment of insomnia and circadian sleep disorders that are non-sedating and non- addictive, with ramelteon being the first nonselective MT1/MT2 melatonin receptor agonist marketed in the United States. Our goal is to design orally active, high affinity, and selective MT1 melatonin receptor agonists with optimal pharmacological, pharmacokinetic, and metabolic profiles to establish proof of concept and to further investigate the effectiveness of this series of compounds in promoting sleep and phase shifting altered circadian rhythms, while minimizing potential side effects due to persistent melatonin receptor desensitization/internalization. Towards these goals we will: 1) Develop computational strategies and chemical syntheses iteratively to identify novel chemical scaffolds (cores) and to improve ligand efficacy and selectivity for MT1 melatonin receptors, with subsequent selection of candidate molecules by a combination of in silico ligand-based discovery using phamacophores, virtual screening, and quantitative structure activity relationship and comparative molecular field analysis; 2) Determine ligand affinity, agonist potency, and receptor selectivity using [125I]-iodomelatonin binding to and stimulation of 35S-GTP- 3-S binding on hMT1 and hMT2 melatonin receptors expressed in mammalian cells; 3) Assess stability, brain penetration, and oral bioavailability of lead compounds; 4) Determine the functional efficacy of lead compounds on MT1 and/or MT2 melatonin receptors expressed in mouse suprachiasmatic nucleus (SCN) brain slices in vitro (i.e., inhibition of neuronal firing, phase shift of circadian rhythms of neuronal firing) and mouse in vivo models (i.e., phase shift activity rhythms onset). This collaborative project between Northwestern and Tougaloo researchers will merge expertise in medicinal chemistry, computational and structure-based drug discovery, and screening in in vitro and in vivo models to assess affinity, potency, and selectivity of lead compounds. Together, we will maximize opportunities for the discovery of much need research tools (i.e., MT1 selective ligands) and functionally active series of lead MT1 melatonin receptor agonists, with future potential for the treatment of insomnia and circadian sleep disorders, such as those observed in delayed sleep phase syndrome, blind individuals, and jet lag. PUBLIC HEALTH RELEVANCE: Sleep disorders due to stress, illness, chronic pain, psychiatric conditions, and poor sleep habits affect 70 million people in the United States, often leading to drowsiness, incoordination, and serious motor vehicle and other accidents. The goal of this proposal is to discover a drug that will mimic the effects of the hormone melatonin, which could be used to promote sleep and to treat sleep disorders caused by depression, Parkinson's disease, blindness, jet lag, shift work, and other related conditions.