Synthesis and dopamine transporter affinity of the four stereoisomers of (+/-)-2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo[2.2.1]heptane.
All four stereoisomers of (+/-)-2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo[2.2. 1]heptane were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter. The in vitro binding affinities (Ki) of the 7-azabicyclo[2.2.1]heptane derivatives were measured in rat caudate-putamen tissue and found to be 100-3000-fold less potent (Ki = 5-96 microM) than cocaine and 2beta-(methoxycarbonyl)-3beta-phenyltropane (2, WIN 35,065-2). Surprisingly, the 3alpha-phenyl isomers (6c, 6d) were more potent than the 3beta-phenyl isomers (6a, 6b). Molecular modeling studies revealed that the rigid 7-azabicyclo[2.2.1]heptane derivatives possess molecular topologies which are significantly different than the molecular topologies of the 2beta-(methoxycarbonyl)-3-phenyltropanes.
Zhang
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C
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, USA.
Izenwasser
S
S
Katz
J L
JL
Terry
P D
PD
Trudell
M L
ML
D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D002421:Caudate Nucleus / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008958:Models, Molecular; D008968:Molecular Conformation; D009419:Nerve Tissue Proteins; D011485:Protein Binding; D011699:Putamen / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*
C112874:2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo(2.1.1)heptane; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014326:Tropanes; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine