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.
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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 |
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