title: Biological evaluation and molecular docking studies of AA3052, a compound containing a μ-selective opioid peptide agonist DALDA and d-Phe-Phe-d-Phe-Leu-Leu-NH2, a substance P analogue.
abstract: The design of novel drugs for pain relief with improved analgesic properties and diminished side effect induction profile still remains a challenging pursuit. Tolerance is one of the most burdensome phenomena that may hamper ongoing opioid therapy, especially in chronic pain patients. Therefore, a promising strategy of hybridizing two pharmacophores that target distinct binding sites involved in pain modulation and transmission was established. Previous studies have led to the development of opioid agonist/NK1 agonist hybrids that produce sufficient analgesia and also suppress opioid-induced tolerance development. In our present investigation we assessed the antinociceptive potency of a new AA3052 chimera comprised of a potent MOR selective dermorphin derivative (DALDA) and an NK1 agonist, a stabilized substance P analogue. We have shown that AA3052 significantly prolonged responses to both mechanical and noxious thermal stimuli in rats after intracerebroventricular administration. Additionally, AA3052 did not trigger the development of tolerance in a 6-day daily injection paradigm nor did it produce any sedative effects, as assessed in the rotarod performance test. However, the antinociceptive effect of AA3052 was independent of opioid receptor stimulation by the DALDA pharmacophore as shown in the agonist-stimulated G-protein assay. Altogether the current results confirm the antinociceptive effectiveness of a novel opioid/SP hybrid agonist, AA3052, and more importantly its ability to inhibit the development of tolerance.
authors.affiliation: Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kowalczyk
authors.affiliation: Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland. Electronic address: hazufiel@wp.pl.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Kleczkowska
authors.affiliation: Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Rękawek
authors.affiliation: Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland.
authors.forename: Kamila
authors.initials: K
authors.lastname: Kulik
authors.affiliation: Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Lesniak
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6701 Szeged, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Erdei
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6701 Szeged, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Borics
authors.affiliation: Research Group of Organic Chemistry, Department of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Martin
authors.affiliation: Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Pawlik
authors.affiliation: Department of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Str., 02-106 Warsaw, Poland.
authors.forename: Andrzej W
authors.initials: AW
authors.lastname: Lipkowski
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6701 Szeged, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Benyhe
authors.affiliation: Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland.
authors.forename: Helena
authors.initials: H
authors.lastname: Makulska-Nowak
authors.affiliation: Research Group of Organic Chemistry, Department of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Ballet
authors.affiliation: Department of Pharmacodynamics, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, 1 Banacha Str., 02-097 Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bujalska-Zadrozny
mesh_terms: D000700:Analgesics / Q000737:chemistry*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D005260:Female; D008297:Male; D062105:Molecular Docking Simulation; D009842:Oligopeptides / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013373:Substance P / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000617221:AA3052; D000700:Analgesics; D009842:Oligopeptides; C063076:tyrosyl-arginyl-phenylalanyl-lysinamide; D013373:Substance P
keywords: Analgesia; DALDA; Hybrid peptide; Substance P; Tolerance