Identification of the First Marine-Derived Opioid Receptor “Balanced” Agonist with a Signaling Profile That Resembles the Endorphins

Abstract

Opioid therapeutics are excellent analgesics, whose utility is compromised by dependence. Morphine (1) and its clinically relevant derivatives such as OxyContin (2), Vicodin (3), and Dilaudid (4) are “biased” agonists at the μ opioid receptor (OR), wherein they engage G protein signaling but poorly engage β-arrestin and the endocytic machinery. In contrast, endorphins, the endogenous peptide agonists for ORs, are potent analgesics, show reduced liability for tolerance and dependence, and engage both G protein and β-arrestin pathways as “balanced” agonists. We set out to determine if marine-derived alkaloids could serve as novel OR agonist chemotypes with a signaling profile distinct from morphine and more similar to the endorphins. Screening of 96 sponge-derived extracts followed by LC-MS-based purification to pinpoint the active compounds and subsequent evaluation of a mini library of related alkaloids identified two structural classes that modulate the ORs. These included the following: aaptamine (10), 9-demethyl aaptamine (11), demethyl (oxy)–aaptamine (12) with activity at the δ-OR (EC50: 5.1, 4.1, 2.3 μM, respectively) and fascaplysin (17), and 10-bromo fascaplysin (18) with activity at the μ-OR (EC50: 6.3, 4.2 μM respectively). An in vivo evaluation of 10 using δ-KO mice indicated its previously reported antidepressant-like effects are dependent on the δ-OR. Importantly, 17 functioned as a balanced agonist promoting both G protein signaling and β-arrestin recruitment along with receptor endocytosis similar to the endorphins. Collectively these results demonstrate the burgeoning potential for marine natural products to serve as novel lead compounds for therapeutic targets in neuroscience research.

Synthesis and pharmacological characterization of ethylenediamine synthetic opioids in human μ‐opiate receptor 1 (OPRM1) expressing cells

“…In summary, our results demonstrate that this in vitro functional assay for hMOR pharmacology provides a foundation from which effects of these agents in humans can be anticipated and they provide a scaffold for the rational design of potentially superior analgesics that better mimic the endogenous opioid system. 14,32 Through our combinatorial approach, we discovered some novel moderately potent hMOR agonists. Whether these novel compounds have different tolerance profiles or addictive potential needs to be further investigated in vivo.…”

Biased Receptor Signaling in Drug Discovery

“…The diminished respiratory depression potential of the opioid analgesic levorphanol (over morphine) has been attributed to its biased signaling profile (lack of b-arrestin2 recruitment) (Le Rouzic et al, 2019). In fact, the dependence liability of oxycodone, hydrocodone/paracetamol, and hydromorphone has been attributed to biased signaling (toward G protein vs. b-arrestin) (Johnson et al, 2017). The cardioprotective and cardiac fibrosis-modulating properties of the adenosine agonist capadenoson (currently in clinical trials) have been attributed to its biased cAMP activity through adenosine 2b receptor activity (Baltos et al, 2017).…”

The apelin-13 peptide protects the heart against apoptosis through the ERK/MAPK and PI3K/AKT signaling pathways.

“…It is well known that peptides produced by proteasome degradation play important protective roles in various diseases and act as endogenous ligands or receptors to mediate varieties of signaling pathways [11]. For example, endorphins are endogenous peptides produced by the body that have similar effects as morphine and analgesics [12]. Cecropins play important roles in the antibacterial activity of Cterminal amides [13].…”