Brominated Cyclodipeptides from the Marine SpongeGeodiabarrettias Selective 5-HT Ligands

Abstract

The brominated cyclodipeptides barettin (cyclo[(6-bromo-8-entryptophan)arginine]) and 8,9-dihydrobarettin (cyclo[(6-bromotryptophan)arginine]) isolated from the marine sponge Geodia barretti have previously been shown to inhibit settlement of barnacle larvae in a dose-dependent manner in concentrations ranging from 0.5 to 25 microM. 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 Ki values being 1.93, 0.34, and 1.91 microM, respectively. 8,9-Dihydrobarettin interacted exclusively with the 5-HT2C receptor with a Ki value of 4.63 microM; 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.

Marine Indole Alkaloids: Potential New Drug Leads for the Control of Depression and Anxiety

“…Several compounds carrying an indole moiety have been reported to possess affinity towards different serotonin receptors: barettin, 8,9-dihydrobarettin,13 tris-indole alkaloids gelliusine A and B,14 and σ-conotoxin 15. Methylaplysinopsin ( 1 ) (Fig.…”

Antioxidant and Anti-Inflammatory Activities of Barettin

“…Previously, barettin was proven to have anti-fouling properties [4,5,6,7] and these properties are thought to be caused by the serotonin-like structure (Figure 1( 1 )) [8,9]. The identification of barettin from G. barretti collected outside Northern Norway was the result of the antioxidant screening project at MabCent-SFI [10].…”

Bioactive Marine Drugs and Marine Biomaterials for Brain Diseases

“…Hedner et al [157] tested two brominated cyclodipeptides from the sponge Geodia barrette Bowerbank for binding different subtypes of 5-HT receptors expressed in HEK-293 cell membranes (5-HT 1A , 5-HT 1D , 5-HT 2A , 5-HT 2C , 5-HT 3A , 5-HT 4, 5-HT 5A, 5-HT 6 and 5-HT 7A ). 8,9-Dihydrobarettin had affinity only for 5-HT 2C ( Ki = 4.63 µM), while barettin binded to 5-HT 2A ( Ki = 1.93 µM), 5-HT 2C ( Ki = 0.34 µM) and 5-HT 4 ( Ki = 1.91 µM).…”