1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors.
Dopamine, serotonin, and norepinephrine are essential for neurotransmission in the mammalian system. These three neurotransmitters have been the focus of considerable research because the modulation of their production and their interaction at monoamine receptors has profound effects upon a multitude of pharmacological outcomes. Our interest has focused on neurotransmitter reuptake mechanisms in a search for medications for cocaine abuse. Herein we describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin trafficking. A subset of compounds had no significant affinity at 5HT1A, 5HT1B, 5HT1C, D1, D2, or D3 receptors. The lead compound, racemic 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one 4a, was resolved into its enantiomers and the S isomer was found to be the most biologically active enantiomer. Among the most potent of these DAT/NET selective compounds are the 1-(3,4-dichlorophenyl)- (4u) and the 1-naphthyl- (4t) 2-pyrrolidin-1-yl-pentan-1-one analogues.
Meltzer
Peter C
PC
Organix Inc., 240 Salem Street, Woburn, Massachusetts 01801, USA. Meltzer@organixinc.com
Butler
David
D
Deschamps
Jeffrey R
JR
Madras
Bertha K
BK
D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D010422:Pentanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018759:Adrenergic Uptake Inhibitors; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010422:Pentanones; D011759:Pyrrolidines; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C509269:1-(3,4-dichlorophenyl)-2-pyrrolidin-1-ylpentan-1-one; C509270:1-naphthalen-2-yl-2-pyrrolidin-1-ylpentan-1-one; C005719:pyrovalerone