Synthesis and receptor binding of N-substituted tropane derivatives. High-affinity ligands for the cocaine receptor.

摘要: The synthesis and pharmacological characterization of a series N-substituted 3-(4-fluorophenyl)tropane derivatives is reported. compounds displayed binding characteristics that paralleled those cocaine, several had substantially higher affinity at cocaine recognition sites. Conjugate addition 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 4a was effected by Zn/HOAc reduction the corresponding 2,2,2-trichloroethyl carbamate give beta-carbomethoxy-3 beta-(4-fluorophenyl)nortropane (5), which alkylated with allyl afford N-allyl analogue, 6. N-propyl 7, prepared catalytic (Pd/C) most potent 4a, tritiated specific activity 81.3 Ci/mmol. ({sup 3}H)4a bound rapidly reversibly caudate putamen membranes; two-component curve typical analogues observed. Equilibrium achieved within h stable for least 4 h. High- low-affinity Kd values observed (4.7 60 nM, respectively) were more than times lower 3}H)cocaine, density sites (Bmax = 50 pmol/g, high, 290 low) two drugs comparable. Nonspecific ofmore » 5-10% total binding.« less