![conference banner](/images/conference-banner.jpeg)
Abstract
Biphalin (Tyr-D-Ala-Gly-Phe-NH-NH<-Phe<-Gly<-D-Ala<-Tyr) is an opioid octapeptide with a dimeric structure based on two identical pharmacophore portions, derived from enkephalins, joined “tail to tail” by a hydrazide bridge. This particular structure enhances the antinociceptive activity of the native enkephalins with an unknown mechanism, probably based on a cooperative binding and improved enzymatic stability. Biphalin has excellent binding affinity for μ and δ receptors and it is a highly potent analgesic, as potent as or more than ethorphine. A definitive explanation of the extraordinary in vivo potency shown by this compound, which has pronounced efficacy in pain modulation, is still not available; it has been suggested, however, that the high agonist activity may be related to its binding mode at both μ and δ opioid receptors. Biphalin has significantly higher potency than other analgesics with novel biological profiles; in particular, most recent data show that biphalin is unlikely to produce dependency in chronic use. In the past 20 years, there have been many attempts to modify its structure to obtain products unaffected by the action of enkephalinases, to enhance its antinociceptive activity and to modify the BBB penetration. In addition, structure-activity relationship studies (SAR) were performed in order to understand the elements responsible for biphalin’s high activity. The aim of the studies reported in this review was to clarify: i) the role of the hydrazide bridge, ii) the role of residues in position 4, 4’ and 3, 3’, iii) the consequences of molecular simplifications (truncation, delection), iv) the consequences of cyclization through a disulfide bridge, v) conjugation with PEG and fluorescet residues, and vi) radiolabeling on Tyr1.
Keywords: Analgesic activity, Biphalin, Dimeric ligands, Enkephalins, μ/δ Mixed opioid agonist, Opioid receptors, peptidomimetics
Mini-Reviews in Medicinal Chemistry
Title:Structure-Activity Relationships of Biphalin Analogs and their Biological Evaluation on Opioid Receptors
Volume: 13 Issue: 1
Author(s): Federica Feliciani, Francesco Pinnen, Azzurra Stefanucci, Roberto Costante, Ivana Cacciatore, Gino Lucente and Adriano Mollica
Affiliation:
Keywords: Analgesic activity, Biphalin, Dimeric ligands, Enkephalins, μ/δ Mixed opioid agonist, Opioid receptors, peptidomimetics
Abstract: Biphalin (Tyr-D-Ala-Gly-Phe-NH-NH<-Phe<-Gly<-D-Ala<-Tyr) is an opioid octapeptide with a dimeric structure based on two identical pharmacophore portions, derived from enkephalins, joined “tail to tail” by a hydrazide bridge. This particular structure enhances the antinociceptive activity of the native enkephalins with an unknown mechanism, probably based on a cooperative binding and improved enzymatic stability. Biphalin has excellent binding affinity for μ and δ receptors and it is a highly potent analgesic, as potent as or more than ethorphine. A definitive explanation of the extraordinary in vivo potency shown by this compound, which has pronounced efficacy in pain modulation, is still not available; it has been suggested, however, that the high agonist activity may be related to its binding mode at both μ and δ opioid receptors. Biphalin has significantly higher potency than other analgesics with novel biological profiles; in particular, most recent data show that biphalin is unlikely to produce dependency in chronic use. In the past 20 years, there have been many attempts to modify its structure to obtain products unaffected by the action of enkephalinases, to enhance its antinociceptive activity and to modify the BBB penetration. In addition, structure-activity relationship studies (SAR) were performed in order to understand the elements responsible for biphalin’s high activity. The aim of the studies reported in this review was to clarify: i) the role of the hydrazide bridge, ii) the role of residues in position 4, 4’ and 3, 3’, iii) the consequences of molecular simplifications (truncation, delection), iv) the consequences of cyclization through a disulfide bridge, v) conjugation with PEG and fluorescet residues, and vi) radiolabeling on Tyr1.
Export Options
About this article
Cite this article as:
Feliciani Federica, Pinnen Francesco, Stefanucci Azzurra, Costante Roberto, Cacciatore Ivana, Lucente Gino and Mollica Adriano, Structure-Activity Relationships of Biphalin Analogs and their Biological Evaluation on Opioid Receptors, Mini-Reviews in Medicinal Chemistry 2013; 13 (1) . https://dx.doi.org/10.2174/1389557511307010011
DOI https://dx.doi.org/10.2174/1389557511307010011 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
Call for Papers in Thematic Issues
Bioprospecting of Natural Products as Sources of New Multitarget Therapies
According to the Convention on Biological Diversity, bioprospecting is the exploration of biodiversity and indigenous knowledge to develop commercially valuable products for pharmaceutical and other applications. Bioprospecting involves searching for useful organic compounds in plants, fungi, marine organisms, and microorganisms. Natural products traditionally constituted the primary source of more than ...read more
Drugs and mitochondria
Mitochondria play a central role in the life and death of cells. They are not merely the center for energy metabolism but are also the headquarters for different catabolic and anabolic processes, calcium fluxes, and various signaling pathways. Mitochondria maintain homeostasis in the cell by interacting with reactive oxygen-nitrogen species ...read more
Mitochondria as a Therapeutic Target in Metabolic Disorders
Mitochondria are the primary site of adenosine triphosphate (ATP) production in mammalian cells. Moreover, these organelles are an important source of reactive oxygen and nitrogen species in virtually any nucleated cell type. The modulation of a myriad of cellular signaling pathways depends on the mitochondrial physiology. Mitochondrial dysfunction is observed ...read more
Natural Products and Dietary Supplements in Alleviation of Metabolic, Cardiovascular, and Neurological Disorders
Metabolic disorders like diabetes, obesity, inflammation, oxidative stress, cancer etc, cardiovascular disorders like angina, myocardial infarction, congestive heart failure etc as well as neurological disorders like Alzheimer’s, Parkinson’s, Epilepsy, Depression, etc are the global burden. They covered the major segment of the diseases and disorders from which the human community ...read more
![Wayfinder Image](/images/wayfinder.jpg)
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Targeting Ion Channels for the Treatment of Glioma
Mini-Reviews in Medicinal Chemistry Effects of LPA and S1P on the Nervous System and Implications for Their Involvement in Disease
Current Drug Targets Nitroimidazole Radiopharmaceuticals in Hypoxia: Part II Cytotoxicity and Radiosensitization Applications
Current Radiopharmaceuticals An Expanding Appreciation of the Role Chemokine Receptors Play in Cancer Progression
Current Pharmaceutical Design Targeting the LINC00324/miR-16-5p/SEPT2 Signaling Cascade is Effective to Reverse Malignant Phenotypes in Glioblastoma
Anti-Cancer Agents in Medicinal Chemistry Meet Our Editorial Board Member
Current Neuropharmacology Molecular Mechanisms of Action of Gas1 and its Possible Therapeutic Applications
Current Signal Transduction Therapy Immune Checkpoint Regulators: A New Era Toward Promising Cancer Therapy
Current Cancer Drug Targets Approaches to Improve Cellular Retention of Radiohalogen Labels Delivered by Internalising Tumour-Targeting Proteins and Peptides
Current Medicinal Chemistry Current View on the Mechanism of Action of Perifosine in Cancer
Anti-Cancer Agents in Medicinal Chemistry Chlorotoxin-Conjugated Nanoparticles for Targeted Imaging and Therapy of Glioma
Current Topics in Medicinal Chemistry The Glioblastoma Problem: Targeting by Combined Medicinal Chemistry Approaches
Current Medicinal Chemistry Geniposide Attenuates Mitochondrial Dysfunction and Memory Deficits in APP/PS1 Transgenic Mice
Current Alzheimer Research Mesenchymal Stem Cells Mediated Drug Delivery in Tumor-Targeted Therapy
Current Drug Delivery Role of Lysine-specific Demethylase 1 and Its Small Molecule Inhibitors in Glioblastoma Multiforme Therapy
Anti-Cancer Agents in Medicinal Chemistry Oxidative and Nitrosative Stress and Immune-inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)
Current Neuropharmacology Genomics and Pharmacogenomics of Brain Disorders
Current Pharmaceutical Biotechnology High Therapeutic Potential for Systemic Delivery of a Liposomeconjugated Herpes Simplex Virus
Current Cancer Drug Targets Modulation of Ischemic Brain Injury and Neuroinflammation by Adenosine A2A Receptors
Current Pharmaceutical Design GRP78 Influences Chemoresistance and Prognosis in Cancer
Current Drug Targets