title: Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter.
abstract: Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different phenyl substituents, have been synthesized and tested in monoamine transporter assays. As predicted from a pharmacophore model, most of the RR/SS diastereomers showed high potency as dopamine reuptake inhibitors. Analogues with a 4-chlorophenyl group and an unbranched initial alkyl atom had consistently enhanced selectivity for the dopamine transporter. The most potent compounds were those with a three- or four-carbon chain. The "inactive" RS/SR diastereomers showed substantial activity when the phenyl substituent was 3,4-dichloro. On a locomotor assay, one compound was found to have a slow onset and a long duration of action. The activity of these compounds provides additional evidence for a conformational/superposition model of methylphenidate with cocaine-like structures. A ketone analogue, obtained by hydrogenating a previously described vinylogous amide, had activity similar to that of methylphenidate.
authors.affiliation: Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts 02115, USA. mfroimowitz@mcphs.edu
authors.forename: Mark
authors.initials: M
authors.lastname: Froimowitz
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Gu
authors.forename: Les A
authors.initials: LA
authors.lastname: Dakin
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Nagafuji
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Kelley
authors.forename: Damon
authors.initials: D
authors.lastname: Parrish
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Aaron
authors.initials: A
authors.lastname: Janowsky
mesh_terms: D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D008774:Methylphenidate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D011869:Radioligand Assay; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D007659:Ketones; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D008774:Methylphenidate