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.
MeSH terms
-
Animals
-
Biological Availability
-
Brain / metabolism
-
Cell Line
-
Cerebral Cortex / metabolism
-
Cricetinae
-
Cricetulus
-
Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
-
Heterocyclic Compounds, 4 or More Rings / chemistry
-
Heterocyclic Compounds, 4 or More Rings / pharmacology
-
Histamine H1 Antagonists / chemical synthesis*
-
Histamine H1 Antagonists / chemistry
-
Histamine H1 Antagonists / pharmacology
-
Humans
-
Hypnotics and Sedatives / chemical synthesis*
-
Hypnotics and Sedatives / chemistry
-
Hypnotics and Sedatives / pharmacology
-
Male
-
Microsomes, Liver / metabolism
-
Radioligand Assay
-
Rats
-
Rats, Sprague-Dawley
-
Receptor, Serotonin, 5-HT2A / metabolism*
-
Serotonin 5-HT2 Receptor Antagonists / chemical synthesis*
-
Serotonin 5-HT2 Receptor Antagonists / chemistry
-
Serotonin 5-HT2 Receptor Antagonists / pharmacology
-
Sleep / drug effects*
-
Sleep Wake Disorders / drug therapy
-
Spiro Compounds / chemical synthesis*
-
Spiro Compounds / chemistry
-
Spiro Compounds / pharmacology
-
Stereoisomerism
-
Structure-Activity Relationship
Substances
-
Heterocyclic Compounds, 4 or More Rings
-
Histamine H1 Antagonists
-
Hypnotics and Sedatives
-
Receptor, Serotonin, 5-HT2A
-
Serotonin 5-HT2 Receptor Antagonists
-
Spiro Compounds