2 research outputs found
Novel and High Affinity 2‑[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors
The development of pharmacotherapeutic
treatments of psychostimulant
abuse has remained a challenge, despite significant efforts made toward
relevant mechanistic targets, such as the dopamine transporter (DAT).
The atypical DAT inhibitors have received attention due to their promising
pharmacological profiles in animal models of cocaine and methamphetamine
abuse. Herein, we report a series of modafinil analogues that have
an atypical DAT inhibitor profile. We extended SAR by chemically manipulating
the oxidation states of the sulfoxide and the amide functional groups,
halogenating the phenyl rings, and/or functionalizing the terminal
nitrogen with substituted piperazines, resulting in several novel
leads such as <b>11b</b>, which demonstrated high DAT affinity
(<i>K</i><sub>i</sub> = 2.5 nM) and selectivity without
producing concomitant locomotor stimulation in mice, as compared to
cocaine. These results are consistent with an atypical DAT inhibitor
profile and suggest that <b>11b</b> may be a potential lead
for development as a psychostimulant abuse medication
Novel and High Affinity 2‑[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors
The development of pharmacotherapeutic
treatments of psychostimulant
abuse has remained a challenge, despite significant efforts made toward
relevant mechanistic targets, such as the dopamine transporter (DAT).
The atypical DAT inhibitors have received attention due to their promising
pharmacological profiles in animal models of cocaine and methamphetamine
abuse. Herein, we report a series of modafinil analogues that have
an atypical DAT inhibitor profile. We extended SAR by chemically manipulating
the oxidation states of the sulfoxide and the amide functional groups,
halogenating the phenyl rings, and/or functionalizing the terminal
nitrogen with substituted piperazines, resulting in several novel
leads such as <b>11b</b>, which demonstrated high DAT affinity
(<i>K</i><sub>i</sub> = 2.5 nM) and selectivity without
producing concomitant locomotor stimulation in mice, as compared to
cocaine. These results are consistent with an atypical DAT inhibitor
profile and suggest that <b>11b</b> may be a potential lead
for development as a psychostimulant abuse medication