NLS-3 (Levophacetoperane or (R,R) Phacetoperane): A Reverse Ester of Methylphenidate: A Literature Review

Background: NLS-3 or (R, R) enantiomer of phacetoperane (levophacetoperane) is the reverse ester of methylphenidate, a well-documented psychostimulant marketed for the treatment of attention-deficit/hyperactivity disorder (ADHD) since the end of 1950s. Launched in Canada and Europe by Specia Rhône-Poulenc and Rhodia, marketed as Lidepran® (8228 R.P.), for the treatment of obesity and depression, phacetoperane became an increasingly popular psychiatric medication from 1959 to 1967. Previous data supported that the stimulant effect of phacetoperane differed from those of other medications acting on the catecholamine system (e.g., methylphenidate, amphetamine), with an advantage of benefit/risk balance. Method: The goal of this study is to characterize the binding profile of NLS-3 using in vitro and in vivo assays and hypothesize potential therapeutic uses considering all available data. Results: A complete binding profile assay confirmed the potential benefit of phacetoperane with a higher benefit/risk compared to other stimulants. NLS-3 synthesis resulted from phenylketone, which is also used for the synthesis of methylphenidate. It differs from that used by Rhône-Poulenc SA laboratories, allowing the possibility of individualizing several enantiomers not synthesized previously. The present review also confirmed extensive clinical use of the compound in almost one thousand children and adolescents in large dose ranges with fewer side effects versus comparative treatments. Furthermore, levophacetoperane was found to be generally well-tolerated by the subjects. Conclusion: NLS-3 could be a safer and more potent alternative to stimulants for patients with ADHD.