Planta Med 2006; 72 - S_031
DOI: 10.1055/s-2006-949764

Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5-HT ligands

E Hedner 1, M Sjögren 1, PA Frändberg 2, T Johansson 2, U Göransson 1, M Dahlström 3, P Jonsson 3, F Nyberg 2, L Bohlin 1
  • 1Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden
  • 2Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, Biomedical Centre, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden
  • 3Department of Marine Ecology, Tjärnö Marine Biological Laboratory, Göteborg University, SE-452 96 Strömstad, Sweden

The production of bioactive compounds by plants, animals and microorganisms has long been exploited in the search for drug candidates to serve as leads in drug development. Traditionally, such bioprospecting for drug candidates has focused on terrestrial microorganisms and plants; the equivalent research in marine systems is in its infancy, but the much larger diversity of major lineages in the sea promises a wealth of new molecular structures with as yet unknown functions. In the ocean, sessile sponges have proved a rich source of bioactive compounds many of which are believed to constitute a chemical defense against predators or foulers aimed at protecting the body surface. We have previously reported on the production of the brominated cyclodipeptides barettin (cyclo[(6-bromo-8-entryptophan)arginine]) and 8,9-dihydrobarettin (cyclo[(6-bromotryptophan)arginine in the marine sponge Geodia barretti Bowerbank and their ability to inhibit settlement of barnacle larvae in a dose-dependent manner [1].

In order to further establish the molecular target and mode of action of these compounds, we investigated their affinity to human serotonin receptors. The tryptophan residue in the barettins resembles that of endogenous serotonin [5-hydroxytryptamine]. A selection of human serotonin receptors, including representatives from all subfamilies (1–7), were transfected into HEK-293 cells. Barettin selectively interacted with the serotonin receptors 5-HT2A, 5-HT2C and 5-HT4 at concentrations close to that of endogenous serotonin, with the corresponding K i values being 1.93µM, 0.34µM and 1.91µM respectively. 8,9-dihydrobarettin interacted exclusively with the 5-HT2C receptor with a K i value of 4.63µM; it failed to show affinity to 5-HT2A and 5-HT4, indicating that the double bond between the tryptophan and arginine residue plays an important role in the interaction with the receptor proteins.

Reference: 1. Sjögren, M. et al. (2004), J. Nat. Prod. 67: 368–372.