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

• Published in: Journal of medicinal chemistry Vol. 47; no. 10; pp. 2624 - 2634
• Main Authors: Yu, Han, Kim, In Jong, Folk, John E, Tian, Xinrong, Rothman, Richard B, Baumann, Michael H, Dersch, Christina M, Flippen-Anderson, Judith L, Parrish, Damon, Jacobson, Arthur E, Rice, Kenner C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 06.05.2004; Amer Chemical Soc
• Subjects: Animals; Autoradiography; Biogenic Amines - metabolism; Biological and medical sciences; Carrier Proteins - metabolism; Chemistry, Medicinal; Crystallography, X-Ray; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins; Extracellular Fluid - metabolism; In Vitro Techniques; Indans - chemical synthesis; Indans - chemistry; Indans - pharmacology; Life Sciences & Biomedicine; Ligands; Medical sciences; Membrane Glycoproteins - metabolism; Membrane Transport Proteins - metabolism; Miscellaneous; Molecular Structure; Nerve Tissue Proteins - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Norepinephrine Plasma Membrane Transport Proteins; Nucleus Accumbens - metabolism; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Science & Technology; Serotonin - metabolism; Serotonin Plasma Membrane Transport Proteins; Stereoisomerism; Structure-Activity Relationship; Symporters - metabolism; AGENT; METHAMPHETAMINE; GBR 12909; NOREPINEPHRINE; DOPAMINE; RECEPTOR; SEROTONIN; RELEASE; IDENTIFICATION; Amphetamine derivatives; Rat; Ligand; Psychotropic; Biological transport; Metamfetamine; Chemical synthesis; Secondary amine; Enantiomer(-); Dopamine; Indan derivatives; CNS stimulant; Serotonin; Rodentia; Organic chlorine compounds; In vitro; Biological activity; Nucleus accumbens; In vivo; Vertebrata; Mammalia; Animal; Biogenic amine; Phenols; Affinity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0305873

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.