Synthesis and ligand binding of eta(6)-(2beta-carbomethoxy-3beta-phenyltropane) transition metal complexes.
The transition metal complexes [eta(6)- (2beta-carbomethoxy-3beta-phenyltropane)]tricarbonylchromium (3) and [eta(6)-(2beta-carbomethoxy-3beta-phenyltropane)] [eta(5)-(pentamethylcyclopentadienyl)]ruthenium(II)triflate (4) were synthesized from 2beta-carbomethoxy-3beta-phenyltropane (2, WIN 35,065) to further elucidate the influence of substituents on the 3beta-aryl on the affinity of the ligand for cocaine-binding sites at the dopamine transporter. The compounds were tested for their ability to displace bound [(3)H]WIN 35,428 (5) from rat caudate putamen tissue and for their ability to inhibit [(3)H]dopamine uptake. The binding affinity for 3 was 2-fold greater than those observed for cocaine (1) and 2, while the binding affinity for 4 was found to be 100-fold less than those of 1 and 2. In addition, 3 was equipotent with 1 and 2 in [(3)H]dopamine uptake inhibition studies, while 4 was 10-fold less potent. The potencies of the complexes 3 and 4 correlated well with the structure-activity relationships of other 2beta-carbomethoxy-3beta-aryltropane derivatives. These data further support a pharmacophore model in which the region occupied by the aryl ring is a lipophilic pocket with electropositive character.
Aronson
B
B
Department of Chemistry, University of New Orleans, Louisiana 70148, USA.
Enmon
J L
JL
Izenwasser
S
S
Katz
J L
JL
Kelkar
S V
SV
Luo
L
L
Nolan
S P
SP
Trudell
M L
ML
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011699:Putamen / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
C100471:(eta(6)-(2-carbomethoxy--3-phenyltropane))(eta(5)-(pentamethylcyclopentadienyl))ruthenium(II) triflate; C100470:(eta(6)-(2-carbomethoxy-3-phenyltropane))tricarbonylchromium; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009942:Organometallic Compounds; D014326:Tropanes; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; C021278:troparil; D003042:Cocaine