Slow-onset, long-duration 3-(3 ',4 '-dichlorophenyl)-1-indanamine monoamine reuptake blockers as potential medications to treat cocaine abuse

A series of 3-(3',4'-dichlorophenyl)-1-indanamine monoamine reuptake blocke rs have been synthesized in an effort to develop a compound that could be u sed as a maintenance therapy to treat cocaine abuse. Since the effects of c ocaine on dopamine (DA) and serotonin (5HT) transporters are important comp onents of its pharmacological activity; the focus was;on nonselective inhib itors of monoamine transport. To reduce or eliminate the abuse potential of a DA reuptake blocker, the compounds were designed to,be slow-onset, long- duration prodrugs whose N-demethylated metabolites would have increased-act ivity over the parent compound with the ideal being a parent compound that has little or no activity.;To achieve this, pairs of compounds with differe nt groups on the amine nitrogen and with and without an additional N-methyl group were synthesized. All of the synthesized compounds were screened for binding and reuptake at the cloned human DA, 5HT, and norepinephrine (NE) transporters. As previously found, trans isomers are nonselective blockers of DA, 5HT, and NE reuptake, cis isomers with small N-alkyl groups are sele ctive blockers of 5HT reuptake, and tertiary amines of the trans compounds are less potent than the corresponding N-demethylated secondary amines as b lockers of,DA reuptake. Larger N-alkyl groups in both the trans and cis ser ies were found to reduce activity for the 5HT and NE transporters-with less effect at DA transporters. Selected trans compounds were also screened for locomotor activity in mice and generalization to a cocaine-like profile in rats. With intraperitoneal administration, all of the trans isomers showed a slow onset of at least 20 min and an extremely long duration of action i n the locomotor assays. Several of the trans compounds also fully generaliz ed to a cocaine-like pharmacological profile. An initial lead compound, the N,N-dimethyl analogue trans-1b was resolved into chirally pure enantiomers . Surprisingly, both enantiomers were found to have significant affinity fo r the DA transporter and to cause locomotor activation This is in contrast to the N-methyl compound in which only the (+)-enantiomer had significant a ctivity. The absolute configuration of the more active enantiomer was deter mined by X-ray crystallography to be 3R,1S.