Synthesis and receptor binding of N-substituted tropane derivatives. High-affinity ligands for the cocaine receptor.
The synthesis and pharmacological characterization of a series of N-substituted 3-(4-fluorophenyl)tropane derivatives is reported. The compounds displayed binding characteristics that paralleled those of cocaine, and several had substantially higher affinity at cocaine recognition sites. Conjugate addition of 4-fluorophenyl magnesium bromide to anhydroecgonine methyl ester gave 2 beta-(carbomethoxy)-3 beta-(4-fluorophenyl)tropane (4a, designated CFT, also known as WIN 35,428) after flash chromatography. N demethylation of 4a was effected by Zn/HOAc reduction of the corresponding 2,2,2-trichloroethyl carbamate to give 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)nortropane (5), which was alkylated with allyl bromide to afford the N-allyl analogue, 6. The N-propyl analogue, 7, was prepared by catalytic reduction (Pd/C) of 6. The most potent analogue, 4a, was tritiated at a specific activity of 81.3 Ci/mmol. [3H]4a bound rapidly and reversibly to caudate putamen membranes; the two-component binding curve typical of cocaine analogues was observed. Equilibrium was achieved within 2 h and was stable for at least 4 h. High- and low-affinity Kd values observed for [3H]4a (4.7 and 60 nM, respectively) were more than 4 times lower than those for [3H]cocaine, and the density of binding sites (Bmax = 50 pmol/g, high, and 290 pmol/g, low) for the two drugs were comparable. Nonspecific binding of [3H]4a was 5-10% of total binding.
Milius
R A
RA
Research Biochemicals Inc., Natick, Massachusetts 01760.
Saha
J K
JK
Madras
B K
BK
Neumeyer
J L
JL
D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins; D055598:Chemical Phenomena; D002621:Chemistry; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium; D014326:Tropanes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D002352:Carrier Proteins; D011955:Receptors, Drug; D014326:Tropanes; C061445:cocaine receptor; D014316:Tritium; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine