Synthesis and biological evaluation of pentacyclo[,6).0(3,10).0(5,9)]undecane derivatives as potential therapeutic agents in Parkinson's disease.


Journal Article

In previous studies, the polycyclic cage amine 8-benzylamino-8,11-oxapentacyclo[,6).0(3,10).0(5,9)]undecane (NGP1-01) and a number of its derivatives showed positive effects in neuroprotection studies with MPTP, in vivo. In view of these findings, we examined these compounds for their effects on [(3)H]dopamine ([(3)H]DA) release and uptake inhibition in murine striatal synaptosomes, as well as for inhibition of baboon liver monoamine oxidase (MAO) B. In order to assess specificity, initial experiments focused on compounds that blocked dopamine uptake without causing appreciable release (<40% at 100 microM) of the transmitter. NGP1-01 blocked the uptake of [(3)H]DA with an IC(50) of 57 microM, while another compound, 8-phenylethyl-8,11-oxapentacyclo[,6).0(3,10).0(5,9)]undecane, blocked uptake at an IC(50) value of 23 microM. These values were comparable to that of another polycyclic cage amine, amantadine (IC(50); 82 micro), that is used in parkinsonian therapy. Structure-activity relationships of this series of compounds support the importance of geometric and steric, rather than electronic effects, in determining biological activity. MAO-B inhibition for this group was weak, with less than 50% inhibition at 300 microM for any of the compounds in the series. The present study suggests that blockage of the dopamine transporter may underlie, at least in part, their neuroprotective effects against MPTP-induced parkinsonism. These compounds may be considered as potential lead compounds for Parkinson's Disease therapy.

Full Text

Duke Authors

Cited Authors

  • Geldenhuys, WJ; Malan, SF; Murugesan, T; Van der Schyf, CJ; Bloomquist, JR

Published Date

  • April 1, 2004

Published In

Volume / Issue

  • 12 / 7

Start / End Page

  • 1799 - 1806

PubMed ID

  • 15028270

Pubmed Central ID

  • 15028270

International Standard Serial Number (ISSN)

  • 0968-0896

Digital Object Identifier (DOI)

  • 10.1016/j.bmc.2003.12.045


  • eng

Conference Location

  • England