title: CoMFA study of novel phenyl ring-substituted 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter.
abstract: A series of phenyl ring-substituted analogues of 3alpha-(diphenylmethoxy)tropane (benztropine) has been prepared as novel probes for the dopamine transporter. Cross-validated comparative molecular field analysis (CoMFA) models of the binding domain on the dopamine transporter were constructed using 37 geometry-optimized structures of these compounds and their corresponding binding affinities (K(i) values) for the displacement of [(3)H]WIN 35,428 or potency of [(3)H]dopamine uptake inhibition (IC(50) values) in rat caudate putamen tissue. The most predictive model (q(2) = 0.78) correlated the steric component of CoMFA to the dependent variable of [(3)H]WIN 35,428 binding affinities. A novel series of seven phenyl ring-substituted analogues of 3alpha-(diphenylmethoxy)tropane was prepared, and our best molecular model was used to accurately predict their binding affinities. This study is the first to provide a CoMFA model for this class of dopamine uptake inhibitors. This model represents an advancement in the design of novel dopamine transporter ligands, based on 3alpha-(diphenylmethoxy)tropane, and further substantiates structure-activity relationships that have previously been proposed for this class of compounds. This CoMFA model can now be used to predict the binding affinities of novel 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter and will be useful in the design of molecular probes within this class of dopamine uptake inhibitors.
authors.affiliation: Psychobiology Section, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Newman
authors.forename: S
authors.initials: S
authors.lastname: Izenwasser
authors.forename: M J
authors.initials: MJ
authors.lastname: Robarge
authors.forename: R H
authors.initials: RH
authors.lastname: Kline
mesh_terms: D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000737:chemistry; D004298:Dopamine / Q000737:chemistry; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000737:chemistry*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008958:Models, Molecular; D009419:Nerve Tissue Proteins; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014326:Tropanes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C116905:3-diphenylmethoxytropane; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014326:Tropanes; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; D004298:Dopamine