title: Steric parameters, molecular modeling and hydropathic interaction analysis of the pharmacology of para-substituted methcathinone analogues.
abstract: OBJECTIVE
  There is growing concern over the abuse of certain psychostimulant methcathinone (MCAT) analogues. This study extends an initial quantitative structure-activity relationship (QSAR) investigation that demonstrated important steric considerations of seven 4- (or para-)substituted analogues of MCAT. Specifically, the steric character (Taft's steric ES ) of the 4-position substituent affected in vitro potency to induce monoamine release via dopamine and 5-HT transporters (DAT and SERT) and in vivo modulation of intracranial self-stimulation (ICSS). Here, we have assessed the effects of other steric properties of the 4-position substituents.
  
  
  METHODS
  Definitive steric parameters that more explicitly focus on the volume, width and length of the MCAT 4-position substituents were assessed. In addition, homology models of human DAT and human SERT based upon the crystallized Drosophila DAT were constructed and docking studies were performed, followed by hydropathic interaction (HINT) analysis of the docking results.
  
  
  RESULTS
  The potency of seven MCAT analogues at DAT was negatively correlated with the volume and maximal width of their 4-position substituents, whereas potency at SERT increased as substituent volume and length increased. SERT/DAT selectivity, as well as abuse-related drug effects in the ICSS procedure, also correlated with the same parameters. Docking solutions offered a means of visualizing these findings.
  
  
  CONCLUSIONS
  These results suggest that steric aspects of the 4-position substituents of MCAT analogues are key determinants of their action and selectivity, and that the hydrophobic nature of these substituents is involved in their potency at SERT.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Sakloth
authors.forename: R
authors.initials: R
authors.lastname: Kolanos
authors.forename: P D
authors.initials: PD
authors.lastname: Mosier
authors.forename: J S
authors.initials: JS
authors.lastname: Bonano
authors.forename: M L
authors.initials: ML
authors.lastname: Banks
authors.forename: J S
authors.initials: JS
authors.lastname: Partilla
authors.forename: M H
authors.initials: MH
authors.lastname: Baumann
authors.forename: S S
authors.initials: SS
authors.lastname: Negus
authors.forename: R A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000818:Animals; D001665:Binding Sites; D050483:Dopamine Plasma Membrane Transport Proteins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D029721:Drosophila Proteins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011427:Propiophenones / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D011619:Psychotropic Drugs / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D012653:Self Stimulation / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism
chemical_list: C493211:DAT protein, Drosophila; D050483:Dopamine Plasma Membrane Transport Proteins; D029721:Drosophila Proteins; D008024:Ligands; D011427:Propiophenones; D011619:Psychotropic Drugs; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C047806:monomethylpropion