Synthesis and 5HT modulating activity of stereoisomers of 3-phenoxymethyl-4-phenylpiperidines.
A series of pairs of enantiomers of substituted 3-phenoxymethyl-4-phenylpiperidines has been prepared from arecoline or alpha-methylstyrene by a combination of stereospecific reactions and optical resolutions. The ability of the compounds to modulate serotonin (5HT) neurotransmission in vitro was determined. Several derivatives, among which is the antidepressant paroxetine, are very potent inhibitors of 5HT reuptake. These compounds exhibit a pronounced steric requirement for inhibition of 5HT reuptake and binding to 5HT2A and 5HT2C receptors.
Engelstoft
M
M
Novo Nordisk A/S, Medicinal Chemistry, Health Care Discovery, Maaloev, Denmark.
Hansen
J B
JB
D000818:Animals; D002417:Cattle; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D010880:Piperidines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors