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Synthesis and biological evaluation of pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane derivatives as potential therapeutic agents in Parkinson's disease.

Abstract：

:In previous studies, the polycyclic cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).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[5.4.0.0(2,6).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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

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

doi

10.1016/j.bmc.2003.12.045

subject

Has Abstract

pub_date

2004-04-01 00:00:00

pages

1799-806

issue

7

eissn

0968-0896

issn

1464-3391

pii

S0968089604000240

journal_volume

12

pub_type

杂志文章

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