title: Identification and characterization of a novel allosteric modulator (SoRI-6238) of the serotonin transporter.
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.
authors.affiliation: Clinical Psychopharmacology Section, Intramural Research Program, National Institute of Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Ayon
authors.initials: A
authors.lastname: Nandi
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Manish
authors.initials: M
authors.lastname: Kulshrestha
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ananthan
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002219:Carbamates / Q000378:metabolism* / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011719:Pyrazines / Q000378:metabolism* / Q000493:pharmacokinetics; D011869:Radioligand Assay; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D013347:Subcellular Fractions; D027981:Symporters / Q000187:drug effects / Q000378:metabolism
chemical_list: D002219:Carbamates; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011719:Pyrazines; D050486:Serotonin Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat; D027981:Symporters; C492927:ethyl 5-amino-3-(3,4-dichlorophenyl)-1,2-dihydropyrido(3,4-b)pyrazin-7-ylcarbamate