Synthesis and Pharmacological Evaluation of 3-(3,4-Dichlorophenyl)-1-indanamine Derivatives as Nonselective Ligands for Biogenic Amine Transporters

In our efforts toward developing a nonselective ligand that would block the effects of stimulants such as methamphetamine at dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporters, we synthesized a series of 3-(3,4-dichlorophenyl)-1-indanamine derivatives. Two of the examined higher affinity compounds had a phenolic hydroxyl group enabling preparation of a medium to long chain carboxylic acid ester that might eventually be useful for a long-acting depot formulation. The in vitro data indicated that (−)-(1R,3S)-trans-3-(3,4-dichlorophenyl)-6-hydroxy-N-methyl-1-indanamine ((−)-(1R,3S)-11) displays high-affinity binding and potent inhibition of uptake at all three biogenic amine transporters. In vivo microdialysis experiments demonstrated that intravenous administration of (−)-(1R,3S)-11 to rats elevated extracellular DA and 5-HT in the nucleus accumbens in a dose-dependent manner. Pretreating rats with 0.5 mg/kg (−)-(1R,3S)-11 elevated extracellular DA and 5-HT by approximately 150% and reduced methamphetamine-induced neurotransmitter release by about 50%. Ex vivo autoradiography, however, demonstrated that iv administration of (−)-(1R,3S)-11 produced a dose-dependent, persistent occupation of 5-HT transporter binding sites but not DA transporter sites.