Synthesis, structural identification, and ligand binding of tropane ring analogs of paroxetine and an unexpected aza-bicyclo[3.2.2]nonane rearrangement product.
The structural requirements for high affinity at the serotonin transporter (5-HTT) have been investigated through the preparation of rigid paroxetine analogs. Tropane-derived analogs (4a-i) of paroxetine (2) were designed and synthesized as potential inhibitors of serotonin reuptake based on the structural and biological similarity between the two compound classes. Overall, the affinity of tropane-derived analogs at the 5-HTT was found to be at least an order of magnitude lower than that of paroxetine and ranged from 2-400nM. The reduced affinity at the 5-HTT may be attributed to the inability of the rigid tropane-derived analogs to adopt conformations favored by the 5-HTT. Within the series of tropane analogs, the 2beta,3beta- and 2beta,3alpha-isomers, 4a and 4d, were the most potent at the DAT and NET and are also significantly more potent than paroxetine (2) suggesting that their reduced conformational flexibility maximizes residence time in conformations favored by these transporters. Examination of the previously published preparation and structural assignment of 4a by additional NMR and X-ray crystallographic data has established that nucleophilic addition to the intermediate 2beta-methanesulfonyloxymethyl-3beta-(4-fluorophenyl)tropane unexpectedly provided the aza-bicyclo[3.2.2]nonane derivative 10a.
Runyon
Scott P
SP
Chemistry and Life Sciences, Research Triangle Institute, 3040 Cornwallis Road, Research Triangle Park, PO Box 12194, North Carolina, NC 27709-2194, USA.
Burgess
Jason P
JP
Abraham
Philip
P
Keverline-Frantz
Kathryn I
KI
Flippen-Anderson
Judy
J
Deschamps
Jeffrey
J
Lewin
Anita H
AH
Navarro
Hernán A
HA
Boja
John W
JW
Kuhar
Michael J
MJ
Carroll
F Ivy
FI
D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D018360:Crystallography, X-Ray; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D017374:Paroxetine / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000473:Alkanes; D001372:Aza Compounds; D001643:Bridged Bicyclo Compounds; D008024:Ligands; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes; D017374:Paroxetine; C017573:nonane