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

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

  1. Synesthesiac
    J. Med. Chem. 1991,34, 1728-1731

    Richard A. Milius,*J Jayanta K. Saha,? Bertha K. Madras,$ and John L. Neumeyer'

    The synthesis and pharmacological characterization of a series of N-substituted 344-fluoropheny1)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 eater gave 2@-(carbomethoxy)-3~-(4 fluorophenyl)tropan(4e a, designated CJT, 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@-carbomethoxy-3~-(4 fluorophenyl)nortropan(e5 ), 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 (B, = 50 pmol/g, high, and 290 pmol/g, low) for the two drugs were comparable. Nonspecific binding of [3H]4a was 510% of total binding.