title: Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues.
abstract: OBJECTIVE
  Methcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure-activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (Es ), electronic (σp ) and lipophilic (πp ) parameters of the para substituents.
  
  
  METHODS
  For neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation.
  
  
  RESULTS
  MCAT and all six para-substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the Es values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation.
  
  
  CONCLUSIONS
  Selectivity for DAT versus SERT in vitro is a key determinant of abuse-related ICSS facilitation by these MCAT analogues, and steric aspects of the para substituent of the MCAT scaffold (indicated by Es ) are key determinants of this selectivity.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Bonano
authors.forename: M L
authors.initials: ML
authors.lastname: Banks
authors.forename: R
authors.initials: R
authors.lastname: Kolanos
authors.forename: F
authors.initials: F
authors.lastname: Sakloth
authors.forename: M L
authors.initials: ML
authors.lastname: Barnier
authors.forename: R A
authors.initials: RA
authors.lastname: Glennon
authors.forename: N V
authors.initials: NV
authors.lastname: Cozzi
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
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D008297:Male; D011427:Propiophenones / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D012653:Self Stimulation / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D015306:Biogenic Monoamines; D050483:Dopamine Plasma Membrane Transport Proteins; D011427:Propiophenones; D050486:Serotonin Plasma Membrane Transport Proteins; C047806:monomethylpropion