GPR18 Inhibiting Amauromine and the Novel Triterpene Glycoside Auxarthonoside from the Sponge-Derived Fungus Auxarthron reticulatum ^[*]

Abstract

The marine sponge-derived fungus Auxarthron reticulatum produces the cannabinoid receptor antagonist amauromine (1). Recultivation of the fungus to obtain further amounts for more detailed pharmacological evaluation of 1 additionally yielded the novel triterpene glycoside auxarthonoside (2), bearing, in nature, a rather rare sugar moiety, i.e., N-acetyl-6-methoxy-glucosamine. Amauromine (1), which inhibited cannabinoid CB₁ receptors (K_i 0.178 µM) also showed antagonistic activity at the cannabinoid-like orphan receptor GPR18 (IC₅₀ 3.74 µM). The diketopiperazine 1 may thus serve as a lead structure for the development of more potent and selective GPR18 antagonists, which are required to study the orphan receptorʼs potential as a new drug target. Despite the execution of many biological assays, to date, no bioactivity could be found for auxarthonoside (2).

Key words

Auxarthron reticulatum - Onygenaceae - marine-derived fungi - GPR18 receptor inhibition

^* Dedicated to Professor Dr. Dr. h. c. mult. Adolf Nahrstedt on the occasion of his 75th birthday.

• References

• 1 Elsebai MF, Rempel V, Schnakenburg G, Kehraus S, Müller CE, König GM. Identification of a potent and selective cannabinoid CB1 receptor antagonist from Auxarthron reticulatum . ACS Med Chem Lett 2011; 2: 866-869
• 2 Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 2010; 62: 588-631
• 3 Balenga NA, Henstridge CM, Kargl J, Waldhoer M. Pharmacology, signaling and physiological relevance of the G protein-coupled receptor 55. Adv Pharmacol 2011; 62: 251-277
• 4 Liu B, Song S, Jones PM, Persaud SJ. GPR55: from orphan to metabolic regulator?. Pharmacol Ther 2015; 145: 35-42
• 5 McHugh D. GPR18 in microglia: implications for the CNS and endocannabinoid system signaling. Br J Pharmacol 2012; 167: 1575-1582
• 6 Altona C, Haasnoot CAG. Prediction of anti and gauche vicinal proton-proton coupling constants in carbohydrates: a simple additivity rule for pyranose rings. Org Magn Reson 1980; 13: 417-429
• 7 Tanaka Y, Sato H, Kageyu A, Tomita T. Separation of geranylgeraniol isomers by highperformance liquid chromatography and identification by 13C nuclear magnetic resonance spectroscopy. J Chromatogr 1985; 347: 275-283
• 8 Wakaka D, Hosoe T, Itabashi T, Fukushima K, Kawai K. Two new glycosides, malfilamentosides A and B, from Malbranchea filamentosa . Mycotoxins 2008; 58: 1-6
• 9 Harms H, Rempel V, Kehraus S, Kaiser M, Hufendiek P, Müller CE, König GM. Indoloditerpenes from a marine-derived fungal strain of Dichotomomyces cejpii with antagonistic activity at GPR18 and cannabinoid receptors. J Nat Prod 2014; 77: 673-677
• 10 Rempel V, Atzler K, Behrenswerth A, Karcz T, Schöder C, Hinz S, Kaleta M, Thimm D, Kiec-Kononowicz K, Müller CE. Bicyclic imidazole-4-one derivatives: a new class of antagonists for the orphan G protein-coupled receptors GPR18 and GPR55. MedChemComm 2014; 5: 632-649
• 11 Krumbein WE, Hoog GS, Urzí C. On the isolation of microcolonial fungi occurring on and in marble and other calcareous rocks. Sci Total Environ 1995; 167: 287-294
• 12 Rempel V, Volz N, Gläser F, Nieger M, Bräse S, Müller CE. Antagonists for the orphan G-protein-coupled receptor GPR55 based on a coumarin scaffold. J Med Chem 2013; 56: 4798-4810