An analysis of the binding of cocaine analogues to the monoamine transporters using tensor decomposition 3-d QSAR.
The conformation and alignment of cocaine analogues bound to the monoamine transporter proteins were explored using the tensor decomposition 3-D QSAR method. It is proposed from these calculations that the bound conformation of these ligands to the three transporter proteins has the 3beta-aryl substituent in a conformation in which the aryl group is orthogonal or approximately orthogonal to the tropane ring. Based on these results, rigid and semi-rigid tropane analogues were designed, synthesized and their affinities for the monoamine transporters were determined.
Appell
Michael
M
Department of Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago, 60612, USA.
Dunn
William J
WJ
Reith
Maarten E A
ME
Miller
Larry
L
Flippen-Anderson
Judith L
JL
D015306:Biogenic Monoamines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D020128:Inhibitory Concentration 50; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters / Q000737:chemistry / Q000378:metabolism
D015306:Biogenic Monoamines; 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; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters; D003042:Cocaine