Isopropylphenidate: An Ester Homolog of Methylphenidate with Sustained and Selective Dopaminergic Activity and Reduced Drug Interaction Liability

Abstract

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. 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. 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. 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.