ABSTRACT
Compounds with combined norepinephrine reuptake inhibitor (NRI) and serotonin 1A (5-HT(1A)) partial agonist pharmacology may offer a new therapeutic approach for treating symptoms of neuropsychiatric disorders including ADHD, depression, and anxiety. Herein we describe the design and optimization of novel chemical matter that exhibits favorable dual NRI and 5-HT(1A) partial agonist activity. Lead compounds in this series were found to be devoid of activity at the dopamine transporter and were shown to be brain penetrant with high receptor occupancy.
Subject(s)
Adrenergic Uptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/pharmacology , Norepinephrine/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists/chemistry , Serotonin 5-HT1 Receptor Agonists/pharmacology , Adrenergic Uptake Inhibitors/pharmacokinetics , Animals , Anxiety/drug therapy , Attention Deficit Disorder with Hyperactivity/drug therapy , Azetidines/chemistry , Azetidines/pharmacokinetics , Azetidines/pharmacology , Brain/metabolism , Depressive Disorder/drug therapy , Dogs , Humans , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Serotonin 5-HT1 Receptor Agonists/pharmacokineticsABSTRACT
Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.
Subject(s)
Adrenergic Uptake Inhibitors/chemical synthesis , Drug Design , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Pyridines/chemical synthesis , Serotonin 5-HT1 Receptor Agonists , Serotonin Receptor Agonists/chemical synthesis , Adrenergic Uptake Inhibitors/metabolism , Adrenergic Uptake Inhibitors/pharmacology , Cell Line , Crystallography, X-Ray , Drug Evaluation, Preclinical/methods , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Phenols/chemical synthesis , Phenols/metabolism , Phenols/pharmacology , Pyridines/metabolism , Pyridines/pharmacology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Receptor Agonists/metabolism , Serotonin Receptor Agonists/pharmacologyABSTRACT
Compounds that are both norepinephrine reuptake inhibitors (NRI) and 5-HT1(A) partial agonists may have the potential to treat neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and depression. Targeted screening of NRI-active compounds for binding to the 5-HT(1A) receptor provided a series of thiomorpholinone hits with this dual activity profile. Several iterations of design, synthesis, and testing led to substituted piperidine diphenyl ethers which are potent NRIs with 5-HT1(A) partial agonist properties. In addition, optimization of these molecules provided compounds which exhibit selectivity for NRI over the dopamine (DAT) and serotonin (SERT) reuptake transporters. Monoamine and 5-HT(1A) in vitro functional activities for select compounds from the developed piperidine diphenyl ether series are also presented.
