Synthesis and biological evaluation of 2-substituted 3beta-tolyltropane derivatives at dopamine, serotonin, and norepinephrine transporters.
A series of eight 2-substituted 3-tolyltropane derivatives were synthesized, and the in vitro and in vivo biological activities as dopamine uptake inhibitors were determined. From the in vitro structure-activity data, it is apparent that a tolyl group in the 2-position, independent of the stereochemical attachment to the tropane ring system, provided compounds (9-12, 14) that exhibit high-affinity binding at the dopamine transporter (DAT). Although a slight stereochemical preference in binding affinity at the DAT was observed for the 2beta-(R)-alcohol 10 over the 2beta-(S)-isomer 11, no significant differences in behavioral effects were observed. Furthermore, despite a relatively low potency of 10 for the inhibition of dopamine uptake compared to its affinity for the DAT, its behavioral profile did not vary significantly from cocaine. These data indicate that a behavioral characterization of compounds is a critical feature of efforts to discover pharmacological treatments for cocaine abuse.
Xu
Lifen
L
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, USA.
Izenwasser
Sari
S
Katz
Jonathan L
JL
Kopajtic
Theresa
T
Klein-Stevens
Cheryl
C
Zhu
Naiju
N
Lomenzo
Stacey A
SA
Winfield
Leyte
L
Trudell
Mark L
ML
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000037:antagonists & inhibitors; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters / Q000378:metabolism*; D014326:Tropanes / Q000138:chemical synthesis* / Q000494:pharmacology
D015306:Biogenic Monoamines; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C493215:Slc6a3 protein, mouse; C493231:Slc6a4 protein, mouse; D027981:Symporters; D014326:Tropanes; D003042:Cocaine; D004298:Dopamine