In vivo antinociception of potent mu opioid agonist tetrapeptide analogues and comparison with a compact opioid agonist-neurokinin 1 receptor antagonist chimera

Autor: Dirk Tourwé, Patrycja Kleczkowska, Muhammad Faheem Asim, Steven Ballet, Andrzej W. Lipkowski, Bart Vandormael, Karel Guillemyn, Isabelle Van den Eynde, Mariana Spetea, Peter W. Schiller, Piotr Kosson, Alexandre Novoa
Rok vydání: 2012
Předmět:
Agonist
Nociception
Time Factors
medicine.drug_class
Receptors
Opioid
mu
Pharmacology
Ligands
lcsh:RC346-429
03 medical and health sciences
Cellular and Molecular Neuroscience
Mice
0302 clinical medicine
Neurokinin-1 Receptor Antagonists
Opioid receptor
medicine
Animals
dual opioid agonist - neurokinin antagonist peptidomimetic
tolerance studies
Opioid peptide
Molecular Biology
lcsh:Neurology. Diseases of the nervous system
030304 developmental biology
0303 health sciences
Analgesics
Tetrapeptide
Dose-Response Relationship
Drug
Morphine
Chemistry
Opioid tetrapeptides
Research
Receptors
Neurokinin-1
Receptor antagonist
Recombinant Proteins
3. Good health
Mice
Inbred C57BL
Opioid
Opioid Peptides
030220 oncology & carcinogenesis
Injections
Intravenous
NK1 receptor antagonist
μ-opioid receptor
Oligopeptides
medicine.drug
Zdroj: Molecular Brain
Molecular Brain, Vol 5, Iss 1, p 4 (2012)
ISSN: 1756-6606
Popis: Background An important limiting factor in the development of centrally acting pharmaceuticals is the blood-brain barrier (BBB). Transport of therapeutic peptides through this highly protective physiological barrier remains a challenge for peptide drug delivery into the central nervous system (CNS). Because the most common strategy to treat moderate to severe pain consists of the activation of opioid receptors in the brain, the development of active opioid peptide analogues as potential analgesics requires compounds with a high resistance to enzymatic degradation and an ability to cross the BBB. Results Herein we report that tetrapeptide analogues of the type H-Dmt1-Xxx2-Yyy3-Gly4-NH2 are transported into the brain after intravenous and subcutaneous administration and are able to activate the μ- and δ opioid receptors more efficiently and over longer periods of time than morphine. Using the hot water tail flick test as the animal model for antinociception, a comparison in potency is presented between a side chain conformationally constrained analogue containing the benzazepine ring (BVD03, Yyy3: Aba), and a "ring opened" analogue (BVD02, Yyy3: Phe). The results show that in addition to the increased lipophilicity through amide bond N-methylation, the conformational constraint introduced at the level of the Phe3 side chain causes a prolonged antinociception. Further replacement of NMe-D-Ala2 by D-Arg2 in the tetrapeptide sequence led to an improved potency as demonstrated by a higher and maintained antinociception for AN81 (Xxx2: D-Arg) vs. BVD03 (Xxx2: NMe-D-Ala). A daily injection of the studied opioid ligands over a time period of 5 days did however result in a substantial decrease in antinociception on the fifth day of the experiment. The compact opioid agonist - NK1 antagonist hybrid SBCHM01 could not circumvent opioid induced tolerance. Conclusions We demonstrated that the introduction of a conformational constraint has an important impact on opioid receptor activation and subsequent antinociception in vivo. Further amino acid substitution allowed to identify AN81 as an opioid ligand able to access the CNS and induce antinociception at very low doses (0.1 mg/kg) over a time period up to 7 hours. However, tolerance became apparent after repetitive i.v. administration of the investigated tetrapeptides. This side effect was also observed with the dual opioid agonist-NK1 receptor antagonist SBCHM01.
Databáze: OpenAIRE
Externí odkaz: