Exploring Pharmacological Activities and Signaling of Morphinans Substituted in Position 6 as Potent Agonists Interacting with the μ Opioid Receptor

Abstract

BackgroundOpioid analgesics are the most effective drugs for the treatment of moderate to severe pain. However, they also produce several adverse effects that can complicate pain management. The μ opioid (MOP) receptor, a G protein-coupled receptor, is recognized as the opioid receptor type which primarily mediates the pharmacological actions of clinically used opioid agonists. The morphinan class of analgesics including morphine and oxycodone are of main importance as therapeutically valuable drugs. Though the natural alkaloid morphine contains a C-6-hydroxyl group and the semisynthetic derivative oxycodone has a 6-carbonyl function, chemical approaches have uncovered that functionalizing position 6 gives rise to a range of diverse activities. Hence, position 6 of N-methylmorphinans is one of the most manipulated sites, and is established to play a key role in ligand binding at the MOP receptor, efficacy, signaling, and analgesic potency. We have earlier reported on a chemically innovative modification in oxycodone resulting in novel morphinans with 6-acrylonitrile incorporated substructures.ResultsThis study describes in vitro and in vivo pharmacological activities and signaling of new morphinans substituted in position 6 with acrylonitrile and amido functions as potent agonists and antinociceptive agents interacting with MOP receptors. We show that the presence of a 6-cyano group in N-methylmorphinans has a strong influence on the binding to the opioid receptors and post-receptor signaling. One 6-cyano-N-methylmorphinan of the series was identified as the highest affinity and most selective MOP agonist, and very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, this MOP agonist showed to be greatly effective against thermal and chemical nociception in mice with marked increased antinociceptive potency than the lead molecule oxycodone.ConclusionDevelopment of such novel chemotypes by targeting position 6 provides valuable insights on ligand-receptor interaction and molecular mode of action, and may aid in identification of opioid therapeutics with enhanced analgesic properties and fewer undesirable effects.

Anacyclus pyrethrum var. pyrethrum (L.) and Anacyclus pyrethrum var. depressus (Ball) Maire: Correlation between Total Phenolic and Flavonoid Contents with Antioxidant and Antimicrobial Activities of Chemically Characterized Extracts

“…Isovaleric acid has a therapeutic effect as an anti-dyslipidemic anticonvulsant [ 42 , 43 , 44 ]. Morphinan-6-one and 4,5α-epoxy-3-hydroxy-17-methyl have analgesic activities [ 45 , 46 ]. Each component may represent different mechanisms of action, whether it reacts individually or synergizes with another, ultimately resulting in many effective therapeutic properties of extracts [ 47 ].…”

Anacyclus pyrethrum (L): Chemical Composition, Analgesic, Anti-Inflammatory, and Wound Healing Properties

“…Pellitorin is an insecticidal, antibacterial, anticancer, anticoagulant, and anti-inflammatory agent [ 47 , 48 , 49 ]. Morphinan-6-One and 4,5.Alpha.-Epoxy-3-Hydroxy-17-Methyl have analgesic activities [ 50 , 51 ]. Isovaleric acid has a therapeutic effect as an antidyslipidemic anticonvulsant [ 3 , 52 , 53 ].…”

Synthesis, Pharmacology, and Molecular Docking Studies on 6-Desoxo-N-methylmorphinans as Potent μ-Opioid Receptor Agonists

“… 10 By targeting the chemically highly versatile 6-keto function of N -methylmorphinan-6-ones, we have reported on a chemically innovative modification giving rise to a novel class of morphinans with acrylonitrile incorporated substructures. 14 The 6-cyano- N -methylmorphinans exhibit high affinity and selectivity for the MOR and potent in vitro and in vivo agonism. 14 …”

“… 14 The 6-cyano- N -methylmorphinans exhibit high affinity and selectivity for the MOR and potent in vitro and in vivo agonism. 14 …”