title: Synthesis, molecular modeling, and biological studies of novel piperidine-based analogues of cocaine: evidence of unfavorable interactions proximal to the 3alpha-position of the piperidine ring.
abstract: A qualitative model for the binding pocket proximal to the 3alpha-substituent of the piperidine-based monoamine transporter ligands was proposed and tested. Based on this model, a new series of druglike 3alpha-modified piperidine-based analogues of cocaine were designed, synthesized, and studied for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE transporters. We found that the insertion of at least one additional methylene group between the piperidine ring and the polar group in the 3alpha-substituent dramatically improves the activity of the compounds that are generally inactive without this additional linker. Molecular modeling analysis showed that the more flexible 3alpha-substituents can avoid unfavorable interactions with the binding sites of DAT, SERT, and NET. The present results may have important implications for the elucidation of the structural differences between DA, 5-HT, and NE transporters and for the further design of new leads for development of cocaine abuse medication as well as certain neurological disorders such as ADHD and depression.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (MC 781), University of Illinois at Chicago, 833 S. Wood Street 539, Chicago, IL 60612, USA. pap4@uic.edu
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Petukhov
authors.forename: Jianrong
authors.initials: J
authors.lastname: Zhang
authors.forename: Cheng Z
authors.initials: CZ
authors.lastname: Wang
authors.forename: Yan Ping
authors.initials: YP
authors.lastname: Ye
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010880:Piperidines; D050486:Serotonin Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat; D027981:Symporters; D003042:Cocaine