Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors

Author(s):Show less -

Kalaba, Predrag ^[1] ; Aher, Nilima Y. ^[1] ; Ilic, Marija ^[1] ; Dragacevic, Vladimir ^[1] ; Wieder, Marcus ^[1] ; Miklosi, Andras G. ^[1] ; Zehl, Martin ^[2] ; Wackerlig, Judith ^[1] ; Roller, Alexander ^[3] ; Beryozkina, Tetyana ^[4] ; Radoman, Bojana ^[1] ; Saroja, Sivaprakasam R. ^[5] ; Lindner, Wolfgang ^[2] ; Gonzalez, Eduardo Perez ^[6] ; Bakulev, Vasiliy ^[4] ; Leban, Johann Jakob ^[1] ; Sitte, Harald H. ^[7] ; Urban, Ernst ^[1] ; Langer, Thierry ^[1] ; Lubec, Gert ^[8]

Affiliation

^[1] Univ Vienna, Dept Pharmaceut Chem, Fac Life Sci, Althanstr 14, A-1090 Vienna - Austria

^[2] Univ Vienna, Dept Analyt Chem, Fac Chem, Wahringer Str 38, A-1090 Vienna - Austria

^[3] Univ Vienna, X Ray Struct Anal Ctr, Fac Chem, Wahringer Str 38, A-1090 Vienna - Austria

^[4] Ural Fed Univ, 19 Mira St, Ekaterinburg 620002 - Russia

^[5] Med Univ Vienna, Dept Pediat, A-1090 Vienna - Austria

^[6] Univ Sao Paulo State, Fac Sci & Technol, Dept Chem & Biochem, Lab Fine Organ Chem, Roberto Simonsen 305, BR-19060900 Presidente Prudente, SP - Brazil

^[7] Med Univ Vienna, Inst Pharmacol, Ctr Physiol & Pharmacol, A-1090 Vienna - Austria

^[8] Paracelsus Med Univ, Neurosci Lab, A-5020 Salzburg - Austria

• Document type: Journal article
• Source: Journal of Medicinal Chemistry; v. 60, n. 22, p. 9330-9348, NOV 23 2017.
• Web of Science Citations: 4

Abstract

Modafinil Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds. (AU)

• FAPESP's process: 16/10149-0 - Synthesis, chemical and biological characterization of 2-phenyl quinazolines-4-substituted analogues as novel atypical dopamine transporter (ADT) and reuptake inhibitors
• Grantee: Eduardo Rene Perez Gonzalez
• Support Opportunities: Scholarships abroad - Research