title: The psychostimulant d-threo-(R,R)-methylphenidate binds as an agonist to the 5HT(1A) receptor.
abstract: The present study was undertaken to determine whether d-threo-(R,R)-methylphenidate (MPH) was exerting binding activity as an agonist or antagonist of 5-HT1A and 5-HT2B receptors. [35S]guanosine5'[gamma-thio]triphosphate ([35S]GTPgammaS) binding assay and field-stimulated Guinea pig ileum assay were used to determine 5-HT(1A) receptor agonism and antagonism activity of d-threo-(R,R)-MPH. The results suggested d-threo-(R,R)-MPH induced 5-HT(1A) receptor agonist activity at 100 microM. The Guinea pig ileum functional assay showed that d-threo-(R,R)-MPH produced agonist-like reduction of neurogenic twitch with an EC50 5.65 +/- 0.36 microM. At 30 microM concentrations, d-threo-(R,R)-MPH produced 171 +/- 4.24% of the relaxation relative to that caused by 0.12 microM 8-OH-DPAT. However, d-threo-(R,R)-MPH exhibited no significant pharmacological activity in rat stomach fundus 5-HT(2B) receptor functional assay. Thus, d-threo-(R,R)-MPH appears to act as a selective 5-HT(1A) receptor agonist in vitro. It is speculated that the activation of 5-HT(1A) receptor might play a partial role in d-threo-(R,R)-MPH mediated dopamine (DA) release in the brain.
authors.affiliation: Laboratory of Drug Disposition and Pharmacogenetics, Department of Pharmaceutical and Biomedical Sciences, Charles P. Darby Children's Research Institute, RM 412, Medical University of South Carolina, Charleston, SC 29425, USA. markowij@musc.edu
authors.forename: J S
authors.initials: JS
authors.lastname: Markowitz
authors.forename: C L
authors.initials: CL
authors.lastname: DeVane
authors.forename: S
authors.initials: S
authors.lastname: Ramamoorthy
authors.forename: Hao-Jie
authors.initials: HJ
authors.lastname: Zhu