Interactions of antidepressants with the serotonin transporter: a contemporary molecular analysis.
One of the most prevalent disorders in present society is depression. The development of treatments for this disorder, beginning with the tricyclic antidepressants and leading to the development of selective serotonin reuptake inhibitors, has focused on compounds that block the function of the serotonin transporter (SERT). In this paper, we have performed Comparative Molecular Field Analysis (CoMFA) using data generated from rat brain synaptosomes and heterologous expression systems expressing rat SERT. Using these models, we have described the molecular requirements for the interactions of antidepressants with SERTs. In addition, molecular studies were performed using chimeric human/Drosophila SERTs and SERT point mutants. These studies focused on identifying regions or discrete amino acids on SERT that may be responsible for recognizing antidepressants.
Roman
David L
DL
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
Walline
Crystal C
CC
Rodriguez
Gustavo J
GJ
Barker
Eric L
EL
D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005473:Fluoxetine / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013574:Synaptosomes / Q000737:chemistry / Q000378:metabolism
D000928:Antidepressive Agents; D002352:Carrier Proteins; D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D005473:Fluoxetine