Discovery and pharmacological characterization of aryl piperazine and piperidine ethers as dual acting norepinephrine reuptake inhibitors and 5-HT1A partial agonists.
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.
Gray
David L
DL
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, United States. david.l.gray@pfizer.com
Xu
Wenjian
W
Campbell
Brian M
BM
Dounay
Amy B
AB
Barta
Nancy
N
Boroski
Susan
S
Denny
Lynne
L
Evans
Lori
L
Stratman
Nancy
N
Probert
Al
A
D004298:Dopamine / Q000378:metabolism; D055808:Drug Discovery; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058825:Serotonin 5-HT1 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004987:Ethers; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; D010880:Piperidines; D058825:Serotonin 5-HT1 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins; D004298:Dopamine