title: Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics.
abstract: As part of our program to study neurotransmitter releasers, we report herein a class of hybrid dopamine reuptake inhibitors that display serotonin releasing activity. Hybrid compounds are interesting since they increase the design potential of transporter related compounds and hence represent a novel and unexplored strategy for therapeutic drug discovery. A series of N-alkylpropiophenones was synthesized and assessed for uptake inhibition and release activity using rat brain synaptosomes. Substitution on the aromatic ring yielded compounds that maintained hybrid activity, with the two disubstituted analogues (PAL-787 and PAL-820) having the most potent hybrid activity.
authors.affiliation: Center for Drug Discovery, Discovery-Science-Technology, RTI International , 3040 Cornwallis Road, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.affiliation: Center for Drug Discovery, Discovery-Science-Technology, RTI International , 3040 Cornwallis Road, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Antonio
authors.initials: A
authors.lastname: Landavazo
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health , Baltimore, Maryland 21224, United States.
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health , Baltimore, Maryland 21224, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: Center for Drug Discovery, Discovery-Science-Technology, RTI International , 3040 Cornwallis Road, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Decker
authors.affiliation: Center for Drug Discovery, Discovery-Science-Technology, RTI International , 3040 Cornwallis Road, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Page
authors.affiliation: Medicinal Chemistry Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health , Baltimore, Maryland 21224, United States.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
keywords: Dopamine uptake inhibitors; cocaine; methamphetamine; serotonin receptor; serotonin releasers