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.
Yu
Han
H
Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, 20892-0815, USA.
Kim
In Jong
IJ
Folk
John E
JE
Tian
Xinrong
X
Rothman
Richard B
RB
Baumann
Michael H
MH
Dersch
Christina M
CM
Flippen-Anderson
Judith L
JL
Parrish
Damon
D
Jacobson
Arthur E
AE
Rice
Kenner C
KC
D000818:Animals; D001345:Autoradiography; D001679:Biogenic Amines / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018360:Crystallography, X-Ray; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D045604:Extracellular Fluid / Q000378:metabolism; D066298:In Vitro Techniques; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009714:Nucleus Accumbens / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism
C486793:3-(3,4-dichlorophenyl)-6-hydroxy-N-methyl-1-indanamine; D001679:Biogenic Amines; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D007189:Indans; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; C493232:Slc6a4 protein, rat; D027981:Symporters; D012701:Serotonin; D004298:Dopamine