Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 7; pp. 1799 - 1802
• Main Authors: Davies, Huw M.L., Hopper, Darrin W., Hansen, Tore, Liu, Quixu, Childers, Steven R.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 05.04.2004; Elsevier
• Subjects: Binding Sites; Biological and medical sciences; Carrier Proteins - metabolism; Catecholaminergic system; Dopamine Plasma Membrane Transport Proteins; Medical sciences; Membrane Glycoproteins - metabolism; Membrane Transport Proteins - metabolism; Methylphenidate - analogs & derivatives; Methylphenidate - chemical synthesis; Methylphenidate - metabolism; Nerve Tissue Proteins - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Protein Binding - physiology; Serotonin Plasma Membrane Transport Proteins; Serotoninergic system; Dopamine; Serotonin; Nitrogen heterocycle; Selectivity; Catecholamine; Naphthalene derivatives; Pyrrolidine derivatives; Serotonin transporter; Structure activity relation; Membrane transport; Piperidine derivatives; Neurotransmitter; Affinity; Chemical synthesis; Methylphenidate; Erythro stereoisomer
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.12.097

The rhodium(II)-catalyzed intermolecular C–H insertion of methyl aryldiazoacetates with either N-Boc-piperidine or N-Boc-pyrrolidine followed by deprotection with trifluoroacetic acid is a very direct method for the synthesis of methylphenidate analogues. By using either dirhodium tetraacetate or dirhodium tetraprolinate derivatives as catalyst, either the racemic or enantioenriched methylphenidate analogues can be prepared. The binding affinities of the methylphenidate analogues to both the dopamine and the serotonin transporters are described. The most notable compounds are the erythro-(2-naphthyl) analogues which display high binding affinity and selectivity for the serotonin transporter. Graphic