GPCR Pharmacological Profiling of Aaptamine from the Philippine Sponge Stylissa sp. Extends Its Therapeutic Potential for Noncommunicable Diseases

Abstract

We report the first isolation of the alkaloid aaptamine from the Philippine marine sponge Stylissa sp. Aaptamine possessed weak antiproliferative activity against HCT116 colon cancer cells and inhibited the proteasome in vitro at 50 µM. These activities may be functionally linked. Due to its known, more potent activity on certain G-protein coupled receptors (GPCRs), including α-adrenergic and δ-opioid receptors, the compound was profiled more broadly at sub-growth inhibitory concentrations against a panel of 168 GPCRs to potentially reveal additional targets and therapeutic opportunities. GPCRs represent the largest class of drug targets. The primary screen at 20 µM using the β-arrestin functional assay identified the antagonist, agonist, and potentiators of agonist activity of aaptamine. Dose-response analysis validated the α-adrenoreceptor antagonist activity of aaptamine (ADRA2C, IC50 11.9 µM) and revealed the even more potent antagonism of the β-adrenoreceptor (ADRB2, IC50 0.20 µM) and dopamine receptor D4 (DRD4, IC50 6.9 µM). Additionally, aaptamine showed agonist activity on selected chemokine receptors, by itself (CXCR7, EC50 6.2 µM; CCR1, EC50 11.8 µM) or as a potentiator of agonist activity (CXCR3, EC50 31.8 µM; CCR3, EC50 16.2 µM). These GPCRs play a critical role in the treatment of cardiovascular disease, diabetes, cancer, and neurological disorders. The results of this study may thus provide novel preventive and therapeutic strategies for noncommunicable diseases (NCDs).

Fluorescence Activity-Guided Isolation of Aaptamine Derivatives From the Marine Sponge Aaptos suberitoides and Their Inhibitory Activity Against Transient Receptor Potential Ankyrin 1

“…The comprehensive screening for the activity of aaptamine on various G-protein coupled receptors (GPCRs) was recently reported. 19 Based on the primary screening on 168 GPCRs, aaptamine was found to be a potent antagonist of β-adrenoreceptor and dopamine receptor D4 with IC 50 values being 0.2 and 6.9 μM, respectively, while an agonist of chemokine receptor 7 (EC 50 6.2 μM). Another study showed that aaptamine and demthylaaptamine have agonistic activity on δ and μ opioid receptors.…”

“…Aaptamine analogs are known to exhibit biological activities 14,15 including antioxidant activity, 16,17 agonistic or antagonistic activity on various proteins, [18][19][20] and growth inhibition of pathogenic microbes 21,22 or cancer cells. 13,21,[23][24][25] The most studied therapeutic area for these compounds is related to anticancer; there are reports describing their effect on the proliferation and progression of cancer cells in detail at the molecular or genetic level.…”

Deep-Sea Sponges and Corals off the Western Coast of Florida—Intracellular Mechanisms of Action of Bioactive Compounds and Technological Advances Supporting the Drug Discovery Pipeline

“…Aaptamine (purified from Stylissa sp.) caused diminished cellular viability in HCT116 colon cancer cells (a 50% reduction, 50 µM, 48 h) [125]. Furthermore, using a betaarrestin assay for screening 169 G-protein coupled receptors (GPCRs) with aaptamine (20 µM) to uncover a pharmacological profile, 13 hits were obtained (CCR1, CXCR7, ADRA2A, ADRA2C, ADRB2, DRD2L, DRD2S, DRD4, CCR3, CXCR3, HTR1E, OPRK1, and SSTR1), which included alpha-adrenoreceptors, beta-adrenoreceptors, and dopamine receptors [125].…”

“…caused diminished cellular viability in HCT116 colon cancer cells (a 50% reduction, 50 µM, 48 h) [125]. Furthermore, using a betaarrestin assay for screening 169 G-protein coupled receptors (GPCRs) with aaptamine (20 µM) to uncover a pharmacological profile, 13 hits were obtained (CCR1, CXCR7, ADRA2A, ADRA2C, ADRB2, DRD2L, DRD2S, DRD4, CCR3, CXCR3, HTR1E, OPRK1, and SSTR1), which included alpha-adrenoreceptors, beta-adrenoreceptors, and dopamine receptors [125]. In a separate report, aaptamine (purified from another sponge, Aaptos aaptos) and its derivatives (9-demethyl aaptamine, demethyl (oxy)-aaptamine, fascaplysin, and 10-bromo-fascaplysin) were tested for their agonist activity towards the µ-OR (opioid receptor) and δ-OR [126].…”