Novel Spirotetracyclic Zwitterionic Dual H₁/5-HT_2A Receptor Antagonists for the Treatment of Sleep Disorders

Abstract

Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.

CNS Physicochemical Property Space Shaped by a Diverse Set of Molecules with Experimentally Determined Exposure in the Mouse Brain

“…Several α-amino acid-like compounds are known to be actively transported across the BBB, as exemplified by gabapentin or L-DOPA, which are transported via the l -type amino acid transporter 1 (LAT-1) . Others are believed to cross the BBB as overall neutral molecules by a passive diffusion mechanism. , However, it should be noted that active transport of α-amino acid-like compounds is very rare and not well understood phenomenon and consequently difficult to translate into a rational CNS drug design.…”

Gan-Dan-Liang-Yi-Tang alleviates p-chlorophenylalanine-induced insomnia through modification of the serotonergic and immune system

“…Therefore, it was hypothesized that the serotonin system was hypnogenic, due to the serotonin-sleep connection. A previous study demonstrated that when serotonin concentration is decreased or following the destruction of the dorsal raphe nuclei in the brainstem, which contain the majority of the serotonergic cell bodies of the brain, sleep is also reduced (25). As reviewed by Dugovic (26), the complex effects of 5-HT in the adjusting on sleep is in part due to the fact that 5-HT may be present in different areas of the brain that are involved in the control of sleep and wakefulness.…”

1,5‐Benzoxazepines as a unique and potent scaffold for activity drugs: A review

“…[55] Compounds with H 1 or 5-HT 2A inverse agonist or antagonist activity have been used in the treatment of insomnia and 33) and its analogues S C H E M E 9 Synthetic route for sorafenib analogues have shown significant pharmacological effects in animal sleep studies. [56] In this study, we present two series of 1,5-benzoxazepine Until the patent publication, a compound with dual activity to both receptors has not been obtained. These compounds can be used for treating sleep disorders characterized by poor sleep maintenance.…”