Structure-activity studies of 3′-4′-dichloro-meperidine analogues at dopamine and serotonin transporters

The structure-activity relationships of 3′,4′-dichloro- meperidine were investigated at dopamine (DAT) and serotonin transporters (SERT). Large ester substituents and lipophilic groups at the 4-position favored molecular recognition at the SERT. The benzyl ester of 3′,4′- dichloro-meperidine exhibited high potency and high selectivity for the SERT (DAT/SERT = 760). Chemical modification of the ester group and N-substitution generally led to compounds with decreased DAT affinity. Only small esters and alkyl groups were tolerated at the 4-position of the meperidine ring system by the DAT. Overall, the meperidine analogues were generally more selective for the SERT than for the DAT.