Design and synthesis of a novel photoaffinity ligand for the dopamine and serotonin transporters based on 2beta-carbomethoxy-3beta-biphenyltropane.
Tropane-based photoaffinity ligands covalently bind to discrete points of attachment on the dopamine transporter (DAT). To further explore structure-activity relations, a ligand in which the photoactivated group was extended from the 3-position of the tropane ring was synthesized from cocaine via a Stille or Suzuki coupling strategy. 3-(4'-Azido-3'-iodo-biphenyl-4-yl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid methyl ester (11; K(i) = 15.1 +/- 2.2 nM) demonstrated high binding affinity for the DAT. Moreover, this compound showed moderate binding affinity for the serotonin transporter (SERT, K(i) = 109 +/- 14 nM), suggesting the potential utility of [(125)I]11 in both DAT and SERT protein structure studies.
Newman
Amy Hauck
AH
Medicinal Chemistry and Psychobiology Sections, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health/DHHS, Baltimore, MD, USA. anewman@intra.nida.nih.gov
Cha
Joo Hwan
JH
Cao
Jianjing
J
Kopajtic
Theresa
T
Katz
Jonathan L
JL
Parnas
M Laura
ML
Vaughan
Roxanne
R
Lever
John R
JR
D003042:Cocaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry*; D015195:Drug Design; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D008024:Ligands; D019920:Photoaffinity Labels / Q000138:chemical synthesis*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry*; D013329:Structure-Activity Relationship
C515238:3-(4'-azido-3'-iodobiphenyl-4-yl)-8-methyl-8-azabicyclo(3.2.1)octane-2-carboxylic acid methyl ester; D050483:Dopamine Plasma Membrane Transport Proteins; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D008024:Ligands; D019920:Photoaffinity Labels; D050486:Serotonin Plasma Membrane Transport Proteins; D003042:Cocaine