Identification and characterization of a novel allosteric modulator (SoRI‐6238) of the serotonin transporter

In the present study we describe a novel agent, SoRI‐6238 (ethyl 5‐amino‐3‐(3,4‐dichlorophenyl)‐1,2‐dihydropyrido[3,4‐ b ]pyrazin‐7‐ylcarbamate) that partially inhibits 5‐HT transporter (SERT) binding and allosterically modulates SERT function. Membranes were prepared from rat brain. SoRI‐6238 partially inhibited SERT binding to brain membranes with a plateau at about 40% of control. SoRI‐6238 fully inhibited norepinephrine transporter (NET) and dopamine transporter (DAT) binding with IC 50 values of 12.1 μM and 5.8 μM, respectively. The apparent K d of [ 125 I]RTI‐55 binding to SERT increased, then reached a plateau with increasing concentrations of SoRI‐6238. SoRI‐6238 fully inhibited [ 3 H]5‐HT uptake, acting to decrease the V max (noncompetitive inhibition). In kinetic experiments, SoRI‐6238 slowed the dissociation of [ 125 I]RTI‐55 from SERT and slowed the initial association rate. We conclude that SoRI‐6238 partially inhibits SERT binding and function, most likely via an allosteric mechanism. Synapse 53:176–183, 2004. © 2004 Wiley‐Liss, Inc.