PYROVALERONE ANALOGS: A PROMISING CLASS OF MONOAMINE UPTAKE INHIBITORS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. We describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. Result: This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin transport. 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, 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)- and the 1-naphthyl- 2-pyrrolidin-1-yl-pentan-1-one analogues. Discussion: The therapeutic potential of pyrovalerones merit consideration, as they differ from tropane analogs of cocaine, and may confer less abuse liability than the tropanes.