Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors

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.