ABSTRACT
Insomnia affects a growing portion of the adult population in the U.S. Most current therapeutic approaches to insomnia primarily address sleep onset latency. Through the 5-hydroxytryptamine(2A) (5-HT(2A)) receptor, serotonin (5-HT) plays a role in the regulation of sleep architecture, and antagonists/inverse-agonists of 5-HT(2A) have been shown to enhance slow wave sleep (SWS). We describe here a series of 5-HT(2A) inverse-agonists that when dosed in rats, both consolidate the stages of NREM sleep, resulting in fewer awakenings, and increase a physiological measure of sleep intensity. These studies resulted in the discovery of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (Nelotanserin), a potent inverse-agonist of 5-HT(2A) that was advanced into clinical trials for the treatment of insomnia.
Subject(s)
Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Serotonin 5-HT2 Receptor Agonists , Sleep Initiation and Maintenance Disorders/drug therapy , Animals , Binding, Competitive , Inhibitory Concentration 50 , Male , Phenylurea Compounds/pharmacokinetics , Pyrazoles/pharmacokinetics , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin/metabolism , Sleep/drug effects , Sleep Initiation and Maintenance Disorders/metabolism , Structure-Activity RelationshipABSTRACT
5-Hydroxytryptamine (5-HT)(2C) receptor agonists hold promise for the treatment of obesity. In this study, we describe the in vitro and in vivo characteristics of lorcaserin [(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3 benzazepine], a selective, high affinity 5-HT(2C) full agonist. Lorcaserin bound to human and rat 5-HT(2C) receptors with high affinity (K(i) = 15 +/- 1 nM, 29 +/- 7 nM, respectively), and it was a full agonist for the human 5-HT(2C) receptor in a functional inositol phosphate accumulation assay, with 18- and 104-fold selectivity over 5-HT(2A) and 5-HT(2B) receptors, respectively. Lorcaserin was also highly selective for human 5-HT(2C) over other human 5-HT receptors (5-HT(1A), 5-HT(3), 5-HT(4C), 5-HT5(5A), 5-HT(6), and 5-HT(7)), in addition to a panel of 67 other G protein-coupled receptors and ion channels. Lorcaserin did not compete for binding of ligands to serotonin, dopamine, and norepinephrine transporters, and it did not alter their function in vitro. Behavioral observations indicated that unlike the 5-HT(2A) agonist (+/-)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT(2A) agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT(2C)-selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT(2A) antagonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (MDL 100,907), demonstrating mediation by the 5-HT(2C) receptor. Chronic daily treatment with lorcaserin to rats maintained on a high fat diet produced dose-dependent reductions in food intake and body weight gain that were maintained during the 4-week study. Upon discontinuation, body weight returned to control levels. These data demonstrate lorcaserin to be a potent, selective, and efficacious agonist of the 5-HT(2C) receptor, with potential for the treatment of obesity.
Subject(s)
Benzazepines/pharmacology , Eating/drug effects , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/pharmacology , Aminopyridines/pharmacology , Animals , Behavior, Animal/drug effects , Benzazepines/blood , Benzazepines/pharmacokinetics , Body Weight/drug effects , Brain/drug effects , Brain/metabolism , Cell Line , Dopamine/metabolism , Fluorobenzenes/pharmacology , Humans , Indoles/pharmacology , Male , Norepinephrine/metabolism , Obesity/drug therapy , Obesity/physiopathology , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2C/physiology , Recombinant Proteins/agonists , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Serotonin/metabolism , Serotonin 5-HT2 Receptor Antagonists , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/blood , Serotonin Receptor Agonists/pharmacokinetics , TransfectionABSTRACT
The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Benzazepines/chemical synthesis , Obesity/drug therapy , Serotonin 5-HT2 Receptor Agonists , Animals , Anti-Obesity Agents/pharmacokinetics , Anti-Obesity Agents/pharmacology , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Cell Line , Eating/drug effects , Humans , Inositol 1,4,5-Trisphosphate/metabolism , Male , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Weight Gain/drug effectsABSTRACT
We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model.
