ABSTRACT
Toidentify new leads for the treatment of Plasmodium
falciparum malaria, we screened a panel of serotonin
(5-hydroxytryptamine [5HT]) receptor agonists and antagonists
and determined their effects on parasite growth. The 5HT1A receptor
agonists 8-hydroxy-N-(di-n-propyl)-aminotetralin
(8-OH-DPAT), 2,5-dimethoxy-4-iodoamphetamine, and
2,5-dimethoxy-4-bromophenylethylamine inhibited the growth of
P. falciparum in vitro (50% inhibitory
concentrations, 0.4, 0.7, and 1.5 μM, respectively). In further
characterizing the antiparasitic effects of 8-OH-DPAT, we found that
this serotonin receptor agonist did not affect the growth of
Leishmania infantum, Trypanosoma
cruzi, Trypanosoma brucei brucei,
or Trichostrongylus colubriformis in vitro and did
not demonstrate cytotoxicity against the human lung fibroblast cell
line MRC-5. 8-OH-DPAT had similar levels of growth inhibition against
several different P. falciparum isolates having distinct
chemotherapeutic resistance phenotypes, and its antimalarial effect was
additive when it was used in combination with chloroquine against a
chloroquine-resistant isolate. In a patch clamp assay, 8-OH-DPAT
blocked a P. falciparum surface membrane channel,
suggesting that serotonin receptor agonists are a novel class of
antimalarials that target a nutrient transport pathway. Since there may
be neurological involvement with the use of 8-OH-DPAT and other
serotonin receptor agonists in the treatment of falciparum malaria, new
lead compounds derived from 8-OH-DPAT will need to be modified to
prevent potential neurological side effects. Nevertheless, these
results suggest that 8-OH-DPAT is a new lead compound with which to
derive novel antimalarial agents and is a useful tool with which to
characterize P. falciparum membrane
channels.
Efficacy of serotonin receptor agonists in the treatment of functional dyspepsia: a meta-analysis
