Synthesis and Receptor Binding of N-Substituted Tropane Derivatives. High-Affinity Ligands for the Cocaine Receptor

Article abstract of DOI:10.1021/jm00109a029

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 2β-(carbomethoxy)-3β-(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 thecorresponding 2,2,2-trichloroethyl carbamate to give 2β-carbomethoxy-3β-(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 K_d 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 (B_max = 50 pmol/g high, and 290 pmol/g, low) for the two drugs were comparable.Nonspecific binding of <3H>4a was 5-10percent of total binding.