Synthesis and dopamine transporter affinity of 2-(methoxycarbonyl)-9-methyl-3-phenyl-9-azabicyclo[3.3.1]nonane derivatives.
A series of 9-methyl-3 beta-phenyl-2-substituted-9-azabicyclo[3.3.1]nonane derivatives were synthesized and evaluated as cocaine-binding site ligands at the dopamine transporter (DAT). The conformation of the bicyclic structures and the stereochemistry of the substituents were determined by NMR and X-ray crystallography. The in vitro binding affinity (Ki) of the 9-azabicyclo[3.3.1]nonane derivatives was measured in rat caudate-putamen tissue, and they were found to be 100-fold (Ki = 2-14 microM) less potent than cocaine and other tropane analogs. From these results it is evident that the cocaine-binding site at the DAT is very sensitive to structural modifications of the unsubstituted methylene bridge [C(6)-C(7)] of cocaine and cocaine-like compounds.
Chen
Z
Z
Department of Chemistry, University of New Orleans, Louisiana 70148, USA.
Izenwasser
S
S
Katz
J L
JL
Zhu
N
N
Klein
C L
CL
Trudell
M L
ML
D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology; D018360:Crystallography, X-Ray; D050483:Dopamine Plasma Membrane Transport Proteins; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008968:Molecular Conformation; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D011485:Protein Binding; D051381:Rats; D011955:Receptors, Drug / Q000378:metabolism
D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011955:Receptors, Drug; C493216:Slc6a3 protein, rat; C061445:cocaine receptor; D003042:Cocaine