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

Synapse. 2004 Sep 1;53(3):176-83. doi: 10.1002/syn.20048.

Abstract

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 microM and 5.8 microM, 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.

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Animals
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Binding, Competitive / drug effects
  • Binding, Competitive / physiology
  • Brain / drug effects*
  • Brain / metabolism
  • Brain Chemistry / drug effects*
  • Brain Chemistry / physiology
  • Carbamates / metabolism*
  • Carbamates / pharmacokinetics
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / metabolism
  • Membrane Transport Proteins / drug effects
  • Membrane Transport Proteins / metabolism
  • Molecular Structure
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurotransmitter Uptake Inhibitors / metabolism*
  • Neurotransmitter Uptake Inhibitors / pharmacokinetics
  • Norepinephrine Plasma Membrane Transport Proteins
  • Pyrazines / metabolism*
  • Pyrazines / pharmacokinetics
  • Radioligand Assay
  • Rats
  • Serotonin Plasma Membrane Transport Proteins
  • Subcellular Fractions
  • Symporters / drug effects
  • Symporters / metabolism

Substances

  • Carbamates
  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Neurotransmitter Uptake Inhibitors
  • Norepinephrine Plasma Membrane Transport Proteins
  • Pyrazines
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a2 protein, rat
  • Slc6a3 protein, rat
  • Slc6a4 protein, rat
  • Symporters
  • ethyl 5-amino-3-(3,4-dichlorophenyl)-1,2-dihydropyrido(3,4-b)pyrazin-7-ylcarbamate