title: Synthesis and monoamine transporter affinity of new 2beta-carbomethoxy-3beta-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency.
abstract: Preparation of cocaine analogues has been aimed largely at development of stable compounds with high affinity and selectivity for the dopamine transporter (DAT). We now report the synthesis and monoamine transporter affinity of 10 new 2beta-carbomethoxy-3beta-[4-(substituted thiophenyl)]phenyltropanes. Among these, compound 4b exhibited very high affinity for the serotonin transporter (SERT: K(i)=17 pM) and good selectivity over dopamine (DAT: 710-fold) and norepinephrine transporters (NET: 11,100-fold).
authors.affiliation: Department of Psychiatry, Yale University and VA Connecticut/116A2, 950 Campbell Avenue, West Haven, CT 06516, USA. gtamagnan@indd.org
authors.forename: Gilles
authors.initials: G
authors.lastname: Tamagnan
authors.forename: David
authors.initials: D
authors.lastname: Alagille
authors.forename: Xing
authors.initials: X
authors.lastname: Fu
authors.forename: Nora S
authors.initials: NS
authors.lastname: Kula
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Baldessarini
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism; D014326:Tropanes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; D014326:Tropanes; C493226:Slc6a2 protein, rat; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat