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 (Ki 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 receptor's potential as a new drug target. Despite the execution of many biological assays, to date, no bioactivity could be found for auxarthonoside (2).

Identification of Novel G Protein–Coupled Receptor 143 Ligands as Pharmacologic Tools for Investigating X-Linked Ocular Albinism

“…A widely applied assay for library screening is the β-arrestin recruitment assay, because many ligands also show (biased) agonism in this assay. 22–26 The assay is well suited for orphan GPCRs, because a positive control is not essential. 27,28 GPR143 colocalizes with β-arrestin 19 ; therefore, we hypothesized that the β-arrestin recruitment assay was suitable for high-throughput screening.…”

Triterpenoids

“…Structure 1 has been proposed for auxarthonoside, a squalene glycoside from the sponge-derived fungus Auxarthron reticulatum. 15 Four derivatives, silphasqualols A 2-D 5, have been found in the compass plant Silphium laciniatum. 16 A compound from cultures of the basidiomycete Antrodiella albocinnamomea apparently has the non-standard structure 6.…”

Quillaic Acid–Containing Saponin-Based Immunoadjuvants Trigger Early Immune Responses

“…Due to this structural composition, saponins are amphiphilic glycoconjugates that make soap-like foams in water that exhibit a number of different biological and pharmacological properties, such as ion channel inhibitory, opioid receptor modulatory, immunomodulatory, antitumor, antiinflammatory, antiviral, antifungal, hypoglycemic, genotoxicity, hypocholesterolemic, and cytotoxicity-enhancing properties. Saponins are commonly used in beverages, confectioneries, and cosmetic and pharmaceutical products (Sparg et al 2004;Arslan et al 2012Arslan et al , 2013Arslan 2014;Arslan 2017;Arslan and Ili 2015;Nazir et al 2015). Saponin not only has stimulating effects on specific immunity components but also results in certain non-specific immune reactions, such as inflammation (Haridas et al 2001;de Oliveira et al 2001) and proliferation of monocytes (Delmas et al 2000;Yui et al 2001).…”