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Antimicrobial Agents and Chemotherapy, December 2003, p. 3806-3809, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3806-3809.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

5HT1A Serotonin Receptor Agonists Inhibit Plasmodium falciparum by Blocking a Membrane Channel

Christopher P. Locher,^1* Peter C. Ruben,^2, Jiri Gut,³ and Philip J. Rosenthal³

Department of Tropical Medicine and Medical Microbiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii 96816,¹ Bekesy Laboratory, Pacific Biomedical Research Corporation, Honolulu, Hawaii 96822,² Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143-0811³

Received 2 June 2003/ Returned for modification 16 July 2003/ Accepted 3 September 2003

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.

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* Corresponding author. Mailing address: Department of Infectious Diseases, Maxygen, Inc., 200 Penobscot Dr., Redwood City, CA 94063. Phone: (650) 298-5487. Fax: (650) 298-5312. E-mail: Christopher.locher{at}maxygen.com.

Present address: PCR, Department of Biology, Utah State University, Logan, Logan, UT 84322.

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Antimicrobial Agents and Chemotherapy, December 2003, p. 3806-3809, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3806-3809.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.