Chemical tools for the opioids

Abstract

The opioids are potent and widely used pain management medicines despite also possessing severe liabilities that have fueled the opioid crisis. The pharmacological properties of the opioids primarily derive from agonism or antagonism of the opioid receptors, but additional effects may arise from specific compounds, opioid receptors, or independent targets. The study of the opioids, their receptors, and the development of remediation strategies has benefitted from derivatization of the opioids as chemical tools. While these studies have primarily focused on the opioids in the context of the opioid receptors, these chemical tools may also play a role in delineating mechanisms that are independent of the opioid receptors. In this review, we describe recent advances in the development and applications of opioid derivatives as chemical tools and highlight opportunities for the future.

Keywords: Adjuvants; Binding affinity; Bioconjugation; Chemical probe; Fluorescence; Hapten; Immunomodulator; Immunotherapeutic; Opioid; Opioid probe; Opioid receptor; Opioid use disorder; Photo-affinity labeling; Photocage; Photopharmacology; Photoswitch; Small molecule; Spatiotemporal control; Vaccine.

Figure 1.. Overview of the opioids and their derivatives.

(a) Structures of common opioid ligands for the opioid receptors; (b) General schematic illustrating biased agonism of opioids at the opioid receptor; (c) Examples of opioid chemical tools highlighted herein.

Figure 2.. Chemical structures of MOR-selective fluorescent tools.

Structure of (a) ([D-Ala², Leu⁵]) enkephalin-Lys-N^ε-Rhod, an enkephalin derivative conjugated to rhodamine; (b) WA-III-62, a para-nitrocinnamoylamino dihydrocodeine (CACO) ligand derivatized with a BODIPY fluorophore; (c) CACO functionalized with Cy3 via a tetraglycine linker. Fluorophores are highlighted in red.

Figure 3.. Chemical structures of DOR selective fluorescent tools.

Structure of (a) ω-BH* DLT-I 5APA, the exorphin deltrophin functionalized with BODIPY at the C-terminus; (b) TIPP-Alexa 488, a synthetic tetrapeptide antagonist of the DOR with Alexa 488 fluorophore; (c) H-Dmt-Tic-Glu-NH-(CH2)5-NH-(C=S)-NH-fluorescein, a synthetic dipeptide antagonist of the DOR with a glycine and fluorescein fluorophore; (d) Dmt-Tic-Lys-IR800CW, a synthetic dipeptide antagonist of the DOR with a fluorophore for in vivo studies. Fluorophores are highlighted in red.

Figure 4.. Chemical structures of KOR selective fluorescent tools.

Structure of (a) m-ICI-199,411-Gly₄-FITC, a non-peptide based fluorescent probe; (b) naltrindole, a DOR selective opioid; (c) 5’-GNTI-Cy3, a naltrindole based KOR selective fluorescent probe. Fluorophores are highlighted in red.

Figure 5.. Chemical structures of non-isoform-selective opioid receptor tools.

Structure of (a) β-naltrexamine, an MOR and DOR agonist; (b) ASM-5–67, a naltrexamine-based probe functionalized with nitrobenzoxadiazole dye; (c) β-funaltrexamine, an irreversible opioid antagonist; (d) NAI-A594, a naltrexamine-based probe utilizing proximity labeling to tag bio molecule with Alexa 594⁶²; (e) morphine-Cy5, a non-opioid isoform selective morphine probe. Fluorophores are highlighted in red, and crosslinking moieties are highlighted in pink.

Figure 6.. Chemical structures of photocaged opioid peptides and alkaloids.

(a) Schematic diagram of a photocaged opioid being activated. Structure of (b) CYLE, Leu-enkephalin functionalized with a carboxy-nitrobenzyl group at the phenolic position; (c) N-MNVOC-LE, Leu-enkephalin functionalized with a nitroveratryloxycarbonyl group at the N-terminus; (d) CNV-Y-DAMGO, synthetic opioid peptide DAMGO with a carboxy-nitroveratryl group at the phenolic position; (e) CNV-NLX, opioid antagonist naloxone with a carboxy-nitroveratryl group at the phenolic position; (f) pc-morphine, opioid agonist morphine with a 7-(diethylamino)-4-(hydroxymethyl) coumarin (DEACM) moiety at the phenolic position. Photocaging moieties are highlighted in orange.

Figure 7.. Chemical structures of photoactivatable opioid tools.

(a) Schematic of opioid photoswitches isomerizing between in the inactive cis conformation and the active trans conformation. Structure of (b) photo-fentanyl (PF2), an azobenzene functionalized fentanyl that photoisomerizes between the inactive cis and active trans states, respectively; (c) photo-fentanyl pyrazole analog, a arylazopyrazole functionalized fentanyl that photoisomerizes between the inactive cis and active trans states, respectively. Photoswitches are highlighted in yellow.

Figure 8.. Chemical structures of crosslinking opioid tools.

(a) Schematic diagram of a crosslinking opioid probe tagging an opioid receptor via ligand directed covalent chemistry. Structure of (b) OPTA-β-NA, a naltrexamine based probe with o-phthalaldehyde as the reactive moiety; (c) PNTI, a naltrindole based probe with o-phthalaldehyde as the reactive moiety; (d) ([D-Ala², Leu⁵]) enkephalin-Lys-N^ε-NAP, a photo affinity labeling probe using a phenylazide; (e) IBNtxA, a novel naltrexamide-based analgesic with an improved side effect profile compared to morphine; (f) alkynyl-IBzA, IBNtxA-based photo affinity labeling probe with click chemistry conjugation compatibility. Crosslinking moieties are highlighted in pink.

Figure 9.. Chemical structures of morphine-based protein bioconjugates.

Structure of (a) morphine conjugated to bovine serum albumin (BSA) from the phenolic position; (b) morphine conjugated to BSA from the 6’ position via a succinate; (c) morphine conjugated to keyhole limpet hemocyanin (KLH) from the 6’ position via a succinate.

Figure 10.. Metabolism of heroin and structure of conjugates for immunization to heroin.

(a) Schematic of the known drug metabolic pathway of heroin.^, Structure of (b) 6-acetylmorphine conjugated to tetanus toxoid via a polyalkylamide linker; (c) heroin or morphine conjugated to KLH; (d) heroin conjugated to tetanus toxoid; (e) morphine conjugated to tetatus toxoid via a PEGylated maleimide linker. Additionally, the V2 loop of HIV-1 glycoprotein 120 envelope protein was cloned into the tetanus toxoid.

Figure 11.. Chemical structures of fentanyl protein bioconjugates.

Structure of (a) the potent opioid agonist fentanyl; (b) fentanyl conjugated to tetanus toxoid via short alkyl linker; (c) fentanyl conjugated to KLH or GMP-grade subunit KLH via a tetraglycine linker.