Synthesis and evaluation of dopamine and serotonin transporter inhibition by oxacyclic and carbacyclic analogues of methylphenidate.
Methylphenidate (Ritalin) binds stereoselectively and enantioselectively to the dopamine transporter (DAT) and inhibits dopamine reuptake with in vitro and in vivo potency similar to that of cocaine. Unlike cocaine, it manifests little, if any, tolerance or addiction liability. Since this compound has a substantial clinical history, it provides an excellent template from which to design potential medications for cocaine abuse. It has long been assumed that a nitrogen, such as exists in cocaine and methylphenidate, is essential for interaction with monoamine transporters. We previously demonstrated that an amine nitrogen in phenyltropane analogues of cocaine is not necessary for conferring high DAT binding affinity. We now report the synthesis of oxacyclic and carbacyclic analogues of methylphenidate, including the four enantiomerically pure isomers of 2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yl)acetic acid methyl ester. The threo isomers are potent and selective inhibitors of the DAT. This is the first generalization of the principle that the presence of nitrogen is not a necessity for DAT inhibition.
Meltzer
Peter C
PC
Organix Inc., 240 Salem Street, Woburn, Massachusetts 01801, USA. Meltzer@organixinc.com
Wang
Pinglang
P
Blundell
Paul
P
Madras
Bertha K
BK
D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002421:Caudate Nucleus / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D008774:Methylphenidate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011699:Putamen / Q000378:metabolism; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D008774:Methylphenidate; D009419:Nerve Tissue Proteins; D010648:Phenylacetates; D011714:Pyrans; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C473679:2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yl)acetic acid methyl ester