Expanding Opioid Receptor Pharmacology: From Pain Control to Novel Therapeutic Applications in Neurobiology, Immunology, and Psychiatry

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: closed (30 April 2026) | Viewed by 924

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Department of Chemistry “G. Ciamician”, University of Bologna, Plesso Navile—Ue4, Via Gobetti 85, 40129 Bologna, Italy
Interests: peptides; peptidomimetics; nitrogen heterocycles; conformational analysis; docking; opioids; integrins; addiction; cancer; biomaterials; diagnostic devices; inflammation
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Dear Colleagues,

Opioid receptors, long studied for their role in pain modulation, are now recognized as key players in a broad range of physiological and behavioral processes. Despite extensive research, the neural circuits, cell types, and dynamics underlying endogenous opioidergic modulation remain incompletely understood, particularly in contexts beyond nociception, such as motivation, stress, and reward. Recent findings suggest that opioid signaling can drive both adaptive and maladaptive behaviors, influencing outcomes in addiction, mood disorders, and chronic stress. The crosstalk between opioids, cannabinoids, and neuroimmune mechanisms further highlights their shared roles in pain and inflammation. New insights into sex-specific responses, epigenetic regulation, and the effects of prenatal opioid exposure deepen our understanding of individual variability in opioid responses. Additionally, novel in vivo tools are enabling real-time analysis of opioid receptor dynamics across brain networks.

Advances in target-guided drug design and AI-enabled discovery are yielding novel ligands, including biased agonists, partial agonists, peripherally acting agonists, and allosteric modulators with improved safety profiles. Concurrently, research into dynorphin–KOP and N/OFQ-NOP systems is expanding the landscape of potential analgesics that avoid the liabilities of traditional opioids.

Together, these advances are reshaping our view of the opioid system—from a narrow focus on analgesia to a multifaceted therapeutic target spanning pain, mood, addiction, and beyond.

Prof. Dr. Luca Gentilucci
Guest Editor

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Keywords

  • opioid
  • pain
  • mood
  • stress
  • addiction
  • neuropeptides

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Published Papers (1 paper)

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Research

21 pages, 6471 KB  
Article
Computational Pharmacodynamic Analysis of Cyclopeptides Derived from c[Trp-Phe-D-Pro-Phe] (CJ-15,208), an Unusual Class of Mixed μ/k-Opioid Receptor Ligands Lacking the Traditional Pharmacophores
by Marco Francescato, Hang Liao, Lorenzo Cavina, Andrea Bedini and Luca Gentilucci
Biomedicines 2026, 14(3), 580; https://doi.org/10.3390/biomedicines14030580 - 5 Mar 2026
Viewed by 668
Abstract
Background: There is currently increasing interest in atypical opioid compounds capable of expanding their clinical applications beyond pain management, including the treatment of psychiatric disorders and substance abuse. In this context, the cyclotetrapeptide c[Trp-Phe-D-Pro-Phe] (CJ-15,208, 1) and its derivatives represent an unusual [...] Read more.
Background: There is currently increasing interest in atypical opioid compounds capable of expanding their clinical applications beyond pain management, including the treatment of psychiatric disorders and substance abuse. In this context, the cyclotetrapeptide c[Trp-Phe-D-Pro-Phe] (CJ-15,208, 1) and its derivatives represent an unusual class of opioid peptides. This compound was found to be a mixed KOR/MOR antagonist in vitro, but it acted as an agonist in vivo. For its diverse analogues, it appeared that receptors’ affinity, selectivity, and agonist/antagonist activity greatly varied upon modifications to backbone geometry and the 3D display of pharmacophores. Methods: We utilized NMR, molecular dynamics, and molecular docking to analyze 3D structures and pharmacodynamic properties of selected representative cyclopeptide analogues of 1. Results: The simulations support that, despite its contradictory functional activity in vitro and in vivo, 1 can bind to the active conformation of receptors in an agonist-like fashion. In general, Trp appeared to be the fundamental pharmacophore in the ligand–receptor complexes. In particular, agonists showed a direct interaction between the indole ring and the carboxylate of the conserved Asp(3:32). Conclusions: These studies support a distinctive pharmacodynamic model for this class of compounds, potentially useful for the design of opioid compounds with novel binding/activity profiles and improved therapeutic effects. Full article
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