Synthesis and monoamine transporter binding properties of 2,3-cyclo analogues of 3beta-(4'-aminophenyl)-2beta-tropanemethanol

J Med Chem. 2006 Jul 27;49(15):4589-94. doi: 10.1021/jm060287w.

Abstract

A series of cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol analogues (5a-m) possessing varying linker groups between the 2- and 3-position on the tropane ring were synthesized and evaluated for their monoamine transporter binding properties. The results show that binding to the dopamine and serotonin transporters (DAT and 5-HTT) is highly dependent on the specific linker used. Cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol pimelic acid ester/amide (5b) had an IC50 of 3.8 nM at the DAT. Cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol sebacic acid ester/amide (5e) had a Ki of 1.9 nM at the 5-HTT and was 68- and 737-fold selective for the 5-HTT relative to the DAT and NET. Small changes to the size as well as the electrostatic and hydrophobic properties of the 2,3-linker in 5b or 5e led to much less potent analogues at all three transporters. These results suggest that the high affinity for 5b and 5e at the DAT and 5-HTT may be due to their specific conformational properties.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Binding, Competitive
  • Cocaine / analogs & derivatives*
  • Cocaine / chemical synthesis
  • Cocaine / chemistry
  • Cocaine / pharmacology
  • Crystallography, X-Ray
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Molecular Structure
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism*
  • Radioligand Assay
  • Rats
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Static Electricity
  • Structure-Activity Relationship
  • Tropanes / chemical synthesis*
  • Tropanes / chemistry
  • Tropanes / pharmacology

Substances

  • 4,5,6,7,8,9,10,11,13,17a,18,19,20,21,22,22a-hexadecahydro-23-methyl-14,17-etheno-19,22-imino-1H-cyclohept(c)(1,9)oxaazacyclononadecine-3,12-dione
  • 5,6,7,8,10,14a,15,16,17,18,19,19a-dodecahydro-20-methyl-11,14-etheno-16,19-iminocyclohept(c)(1,9)oxaazacyclohexadecine-3,9(1H,4H)-dione
  • Dopamine Plasma Membrane Transport Proteins
  • Norepinephrine Plasma Membrane Transport Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Tropanes
  • Cocaine