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).

• Authors: Harmie Luyao, Hendrik Luesch, Mylene Uy
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 26 Issue 18 (Sep 16 2021) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 34577088 (Publication Type: Journal Article)

Chemical References

• Adrenergic Antagonists
• Alkaloids
• Dopamine Antagonists
• Naphthyridines
• Receptors, Adrenergic
• Receptors, Chemokine
• Receptors, Dopamine
• Receptors, G-Protein-Coupled
• aaptamine

Topics

• Adrenergic Antagonists (pharmacology)
• Alkaloids (chemistry, isolation & purification, pharmacology)
• Allosteric Regulation (drug effects)
• Animals
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dopamine Antagonists (pharmacology)
• Humans
• Naphthyridines (chemistry, isolation & purification, pharmacology)
• Noncommunicable Diseases (drug therapy)
• Philippines
• Porifera (chemistry)
• Receptors, Adrenergic (drug effects)
• Receptors, Chemokine (agonists, drug effects)
• Receptors, Dopamine (drug effects)
• Receptors, G-Protein-Coupled (agonists, antagonists & inhibitors, drug effects)
• Saccharomyces cerevisiae (drug effects)