Substance P plays an important role in pain signals generation and transmission from periphery to CNS. In contrast, opioids suppress pain signals mainly through suppression of substance P release. These mechanisms of neurophysiological actions were fundamentals for invention of hybrid compounds that act as both antagonists of substance P to reduce postsynaptic activation of NK1 receptors as well as opioid agonists to activate presynaptic opioid receptors that result in decrease substance P release. It is known that on the surface of tumor cells an overexpression of NK-1 receptors is observed. Literature has reported that antagonists of substance P inhibit proliferation and migration of tumor cells, and reduced tumor angiogenesis. Therefore, to the list of already synthesized and characterized compounds we appended new series of compounds that combine peptide opioid pharmacophore with 3,5 bis-trifluoromethyl-benzyl derivative, responsible for antagonist at NK1 receptor.  In literature  we can found bifunctional peptides which can act through both opioids and NK 1 receptors . A new compound, synthesized our laboratory, was constructed from one part of biphalin and  Z- Trp on the C-terminus (1). In the other team was synthesised similar hybrid which was modified on C-terminus by fragment with 3,5- bistrifluoromethyl- benzyl group (2). On this basis we design, synthesized and tested new bifunctional peptides.

New compounds exhibit high affinity to opioid receptors and decrease viability of human melanoma cells. In in vivo studies hybrids exhibit analgesic activity also.

Therefore peptide analogues as a new type of effective analgesic especially designed for chronic cancer pain treatment has been developed.

References:

1. Bonney, I. M.; Foran, S. E.; Marchand, J. E.; Lipkowski, A. W.; Carr, D. B. Spinal antinociceptive effects of AA501, a novel chimeric peptide with opioid receptor agonist and tachykinin receptor antagonist moieties. Eur. J. Pharmacol. 2004, 488,91–99

2. Ballet S., Feytens D., Buysse K., Chung N.N., Lemieux C., Tumati S., Keresztes A., Duppen J.V., Lai J., Varga E. , Porreca F. , Schiller P. W., Broeck J. V., and Tourwé D. Design of Novel Neurokinin 1 Receptor Antagonists Based on Conformationally Constrained Aromatic Amino Acids and Discovery of a Potent Chimeric Opioid Agonist-Neurokinin 1 Receptor Antagonist. J. Med. Chem. 2011, 54 (7), 2467–2476.

Acknowledgement: This work was supported by the Polish National Science Center (NCN), DEC-2011/03/N/ST5/04725.This work has been supported with a scholarship from the European Social Fund, Human Capital Operational Programme for the execution of the project “Support for bio tech med scientists in technology transfer”; (UDA-POKL.08.02.01-14-041/09).This research has been co-financed with the European Union funds by the European Social Fund.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/31096 must be provided.

1. Sex differences in the opioid component of swim stress-induced analgesia in mouse lines selected for high or low sensitivity to stress
2. Efficacy of Viburnum opulus fruit juice and its components against herpesvirus
3. Keratin Associeted Proteins as a New Type of Bandage for Wound Healing
4. Development of new multitarget GPCRs ligands (opioid agonist- tachykinin antagonist).
5. Anticancer properties of hair proteins digestive peptides
6. Effects D-tryptophan substitutions on the activity and toxicity of antimicrobial dendrimers
7. Novel amphiphilic dendrimers as antibacterial and antitumoral agents.
8. CLA derivatives as functional food compounds
9. Keratin associated proteins (KAPs) as a new biomaterials for applications in medicine and cosmetology
10. Natural compositions with antioxidative properties
11. Application of fermentation in protein hydrolysates utilisation 
12. Comparable antinociceptive effect of biphalin in mice selected for high and low swim stress-induced analgesia after blood-brain barrier disruption caused by hyperosmolar mannitol administration
13. Application of preparative HPLC for protected peptide purification
14. New tachykinin-opioid chimeric analogues as potential new analgesics
15. Spinal cord peptide epitopes ameliorate immunological reaction in  experimental allergic encephalomyelitis /eae/
16. Dendrimeric peptides with  affinity to opioid receptors - complexation properties
17. Development of dendrimeric somatostatin analogues
18. Assessment of analgesic potency of biphalin in a mouse model of cancer pain  
19. H-Dmt-D-Lys-Phe-Phe-OH, a tetrapeptide metabolite of the opioid-neurotensin hybrid peptide PK20, expresses high antinociception
20. THERMOSENSITIVE TRI-BLOCK-CO-POLY- MERS POLY- (HPMAm-MONO/DI LACTATE)- PEG-POLY(HPMAm-MONO/DI LACTATE) FOR THE CONTROLLED RELEASE OF OPIOID PEPTIDES
21. HYDROLISATE OF PIG SPINAL CORD AS A NUTRACEUTIC IN MULTIPLE SCLEROSIS.
22. KERATINE PREPARATIONS FOR WOUND HEALING
23. DEVELOPMENT OF NEW TACHYKININ-OPIOID CHIMERIC ANALOGUES AS POTENTIAL NEW ANALGESIC
24. OPIOID PEPTIDE ANALOGUE AA2016 IN MOUSE MODEL OF INDIVIDUAL PAIN SENSITIVITY
25. A SIMPLE PREPARATIVE HPLC ISOLATION OF CONJUGATED LINOLEIC ACIDS (CLAs).
26. SEARCH FOR NEW ANTIMICROBIAL PEPTIDES FROM HYDROLIZATES OF SEED PROTEINS.