title: Isopropylphenidate: an ester homolog of methylphenidate with sustained and selective dopaminergic activity and reduced drug interaction liability.
abstract: OBJECTIVE
  The most widely utilized pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD) is the psychostimulant methylphenidate (MPH). Most MPH formulations consist of the racemic mixture of d-threo-(R, R)-MPH and l-threo-(S, S)-MPH isomers. MPH is characterized by its low bioavailability and short half-life (2-3 hours). Additionally, significant inter-individual variability in MPH pharmacokinetics has been consistently documented. Accordingly, efforts have been directed at developing alternatives to MPH as therapeutic agents. A wide range of MPH analogues (dl-α-[2-piperidyl]-phenylacetic acid esters) have been synthesized with the dopamine transporter (DAT) and norepinephrine transporter (NET) as principle neuropharmacological targets. The present study investigated the metabolic profiles and pharmacological activity of the isopropyl ester derivative of MPH, dl-isopropylphenidate (IPH), both in vitro and in vivo.
  
  
  METHODS
  The synthesis, monoaminergic transporter binding, cellular uptake profiles, and assessment of metabolic hydrolysis and transesterification in the presence of ethanol are described using MPH as a comparator. Additionally, an in vivo assessment of IPH stimulant effects (vs. saline) in rats was performed with locomotor activity as a pharmacodynamic outcome.
  
  
  RESULTS
  IPH displayed unique pharmacological characteristics including greater DAT than NET binding and cellular uptake activity, and greater resistance to hydrolysis and transesterification via carboxylesterase 1 relative to MPH. Further, sustained psychostimulant properties offer the prospect of an enhanced duration of action.
  
  
  CONCLUSIONS
  Our findings are consistent with IPH exhibiting attributes distinguishing it from MPH and warranting further study and development of IPH as a novel psychotherapeutic agent.
authors.affiliation: 1 Department of Pharmacotherapy and Translational Research, University of Florida , Gainesville, Florida.
authors.forename: John S
authors.initials: JS
authors.lastname: Markowitz
authors.forename: Hao-Jie
authors.initials: HJ
authors.lastname: Zhu
authors.forename: Kennerly S
authors.initials: KS
authors.lastname: Patrick
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D006868:Hydrolysis; D008297:Male; D008774:Methylphenidate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C000592015:isopropylphenidate; D008774:Methylphenidate