Effects of N-substituted analogs of benztropine:: Diminished cocaine-like effects in dopamine transporter ligands

Previous studies demonstrated that analogs of benztropine (BZT) possess high affinity for the dopamine transporter, inhibit dopamine uptake, but generally have behavioral effects different from those of cocaine. One hypothesis is that muscarinic-M-1 receptor actions interfere with cocaine-like effects. Several tropane-nitrogen substitutions of 4', 4"-diF-BZT have reduced M-1 affinity compared with the CH3-analog (AHN 1-055; 3alpha-[bis-(4-fluorophenyl)methoxy]tropane). All of the compounds displaced [H-3]WIN 35,428 (2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane) binding with affinities ranging from 11 to 108 nM. Affinities at norepinephrine ([H-3] nisoxetine) and serotonin ([H-3] citalopram) transporters ranged from 457 to 4810 and 376 to 3260 nM, respectively, and at muscarinic M-1 receptors ([H-3] pirenzepine) from 11.6 (AHN 1-055) to higher values, reaching 1030 nM for the other BZT-analogs. Cocaine and AHN 1-055 produced dose-related increases in locomotor activity in mice, with AHN 1-055 less effective than cocaine. The other compounds were ineffective in stimulating activity. In rats discriminating cocaine (29 mumol/kg i.p.) from saline, WIN 35,428 fully substituted for cocaine, whereas AHN 1-055 produced a maximal substitution of 79%. None of the other analogs fully substituted for cocaine. WIN 35,428 produced dose-related leftward shifts in the cocaine dose-effect curve, whereas selected BZT analogs produced minimal changes in the effects of cocaine. The results suggest that reducing M-1 affinity of 4', 4"-diF-BZT with N-substitutions reduces effectiveness in potentiating the effects of cocaine. Furthermore, although the BZT-analogs bind with high affinity at the dopamine transporter, their behavioral effects differ from those of cocaine. These compounds have reduced efficacy compared with cocaine, a long duration of action, and may serve as leads for the development of medications to treat cocaine abuse.