Synthesis, Monoamine Transporter Binding Properties, and Behavioral Pharmacology of a Series of 3β-(Substituted phenyl)-2β-(3'-substituted isoxazol-5-yl)tropanes

摘要

Several 3β-(substituted phenyl)-2β-(3-substituted isoxazol-5-yl)tropanes (3a-t) were evaluated for their ability to inhibit radioligand binding at the DAT, 5-HTT, and NET as well as in gross observation and locomotor activity in mice and in rats trained to discriminate cocaine. All compounds showed high affinity for the DAT. The IC_(50) values ranged from 0.5 to 26 nM. With the exception of 3e and 3f, which have no substituent on the 2β-(1,2-isoxazole) ring, all compounds were selective for the DAT relative to the 5-HTT and NET. No compound showed death when dosed at 100 mg/kg; however, most compounds did show signs typical of dopamine activity. The ED_(50) values for 2β-(1,2-isoxazoles) that caused locomotor stimulation ranged from 0.2 to 12.8 mg/kg. Most compounds showed slower on-set and longer duration of action relative to cocaine. Surprisingly, 3β-(4-methylphenyl)-2β-[3-(4'-chlorophenyl)isoxazol-5-yl]tropane (3p) and 3β-(4-methylphenyl)-2β-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (3r) did not produce significant increases in locomotor activity. In the cocaine discrimination test, all analogues showed full or at least 50% generalization with the exception of 3p, which did not show generalization. Importantly, both the locomotor activity and the cocaine discrimination ED_(50) values were correlated with the DAT binding but not 5-HTT and NET binding. This provides further support for the dopamine hypothesis of cocaine abuse. High DAT affinity and selectivity, increased locomotor activity with slow onset and long duration of action, and generalization to cocaine shown by the 3β-(substituted phenyl)-2β-(3-substituted isoxazol-5-yl)tropanes are properties thought necessary for a pharmacotherapy for treating cocaine abuse.