7 research outputs found
Tryptophan replacement in the nociceptin/orphanin FQ receptor ligand Ac-RYYRWK-NH2
In the present study we describe the in vitro
pharmacological characterization of the nociceptin/orphanin FQ
(N/OFQ) receptor (NOP) ligand Ac-RYYRWK-NH2 and the synthesis
and biological evaluation of 13 Trp5 substituted Ac-RYYRWK-NH2
analogs. Results indicate that Ac-RYYRWK-NH2 behaves as a highly
potent and selective partial agonist at the NOP receptors and that
the whole indole moiety of the Trp5 side chain is not required,
being a phenyl-ethyl side chain already sufficient for maintaining
high potency
Structure-activity relationship study on human urotensin II
The vasoactive cyclic undecapeptide urotensin-II (U-II) has been identified as an endogenous ligand for the G-protein
coupled receptor now referred to as the UT receptor. The U-II/UT receptor system might be relevant for cardiovascular functions.
A structure-activity study of human U-II investigating 31 peptides in the rat aorta bioassay is reported. Ala- and D-scan
investigations indicated that the sequence Phe6-Trp7-Lys8-Tyr9 is essential for biological activity and that Lys8 and Tyr9 are
particularly important. These two residues were substituted with a series of coded and non-coded amino acids. These studies
demonstrated that the positive charge of the primary aliphatic amine at position 8 and its relative spatial orientation is crucial
for both receptor occupation and activation, while the only chemical requirement at position 9 is the presence of an aromatic
moiety. Moreover, this study led to the identification of UT receptor partial agonists (compounds 23 and 24) which can be used
as chemical templates for further investigations aimed at the identification of selective antagonists
Tryptophan replacement in the nociceptin/orphanin FQ receptor ligand Ac-RYYRWK-NH2
reserved9noThis work was supported by funds from the University of Ferrara (60% grants to GC and SS), the Italian Ministry of the University (FIRB 2001 and Cofin 2004 grant to DR and SS), and the National Institute of Health (RO1HL71212 grant to DR and SS).In the present study we describe the in vitro pharmacological characterization of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) ligand Ac-RYYRWK-NH2 and the synthesis and biological evaluation of 13 Trp5 substituted Ac-RYYRWK-NH2 analogs. Results indicate that Ac-RYYRWK-NH2 behaves as a highly potent and selective partial agonist at the NOP receptors and that the whole indole moiety of the Trp5 side chain is not required, being a phenyl-ethyl side chain already sufficient for maintaining high potency.mixedCARRA' G; CALO' G; SPAGNOLO B; R. GUERRINI; ARDUIN M; MARZOLA E; TRAPELLA C; REGOLI D; SALVADORI SCarra', Giacomo; Calo', Girolamo; Spagnolo, Barbara; Guerrini, Remo; Arduin, Marika; Marzola, Erika; Trapella, Claudio; Regoli, Domenico; Salvadori, Sever
Synthesis and biological activity of nociceptin/orphanin FQ analogues substituted in position 7 or 11 with C alpha,alpha-dialkylated amino acids
Previous structure-activity and NMR studies on nociceptin/orphanin FQ (N/OFQ) demonstrated that Aib substitution
of Ala7 and/or Ala11 increases the peptide potency through an alpha helix structure induction mechanism. On these bases we synthesised
and evaluated pharmacologically in the mouse vas deferens assay a series of N/OFQ-NH2 analogues substituted in position
7 and 11 with Ca,a-disubstituted cyclic, linear and branched amino acids. None of the 20 novel N/OFQ analogues produced better
results than [Aib7]N/OFQ-NH2. Thus, this substitution was combined with other chemical modifications known to modulate peptide
potency and/or efficacy generating compound 21 [Nphe1Aib7Arg14Lys15]N/OFQ-NH2 (coded as UFP-111), compound 22
[(pF)Phe4Aib7Arg14Lys15]N/OFQ-NH2 (UFP-112) and compound 23 [Phe1W(CH2-NH)Gly2(pF)Phe4Aib7Arg14Lys15]N/OFQNH2
(UFP-113). These novel peptides behaved as highly potent NOP receptor ligands showing full (UFP-112) and partial
(UFP-113) agonist and pure antagonist (UFP-111) activities in a series of in vitro functional assays performed on pharmacological
preparations expressing native as well as recombinant NOP receptors
Synthesis and biological activity of nociceptin/orphanin FQ analogues substituted in position 7 or 11 with C alpha,alpha-dialkylated amino acids
Previous structure–activity and NMR studies on nociceptin/orphanin FQ (N/OFQ) demonstrated that Aib substitution of Ala7 and/or Ala11 increases the peptide potency through an alpha helix structure induction mechanism. On these bases we synthesised and evaluated pharmacologically in the mouse vas deferens assay a series of N/OFQ-NH2 analogues substituted in position 7 and 11 with Cα,α-disubstituted cyclic, linear and branched amino acids. None of the 20 novel N/OFQ analogues produced better results than [Aib7]N/OFQ-NH2. Thus, this substitution was combined with other chemical modifications known to modulate peptide potency and/or efficacy generating compound 21 [Nphe1Aib7Arg14Lys15]N/OFQ-NH2 (coded as UFP-111), compound 22 [(pF)Phe4Aib7Arg14Lys15]N/OFQ-NH2 (UFP-112) and compound 23 [Phe1Ψ(CH2–NH)Gly2(pF)Phe4Aib7Arg14Lys15]N/OFQ-NH2 (UFP-113). These novel peptides behaved as highly potent NOP receptor ligands showing full (UFP-112) and partial (UFP-113) agonist and pure antagonist (UFP-111) activities in a series of in vitro functional assays performed on pharmacological preparations expressing native as well as recombinant NOP receptors
N- and C-terminal modifications of nociceptin/orphanin FQ generate highly potent NOP receptor ligands
Previous structure-activity studies on nociceptin/orphanin FQ (N/OFQ) identified [Phe1\ube(CH2-
NH)Gly2]N/OFQ(1-13)-NH2 and [Nphe1]N/OFQ(1-13)-NH2 as a N/OFQ peptide receptor (NOP)
partial agonist and pure antagonist, respectively. The addition of fluorine to the Phe4 or the
insertion of a further pair of basic amino acids Arg14-Lys15 generate potent agonists. On the
basis of these findings, we combined in the N/OFQ-NH2 template the chemical modifications
Arg14-Lys15 and (pF)Phe4 that increase the agonist potency with those conferring partial agonist
(Phe1\ube(CH2NH)Gly2) or pure antagonist (Nphe1) properties. Twelve peptides were synthesized
and pharmacologically evaluated in Chinese hamster ovary cells expressing the human
recombinant NOP and in electrically stimulated mouse vas deferens and guinea pig ileum
assays. All peptides behaved as NOP ligands; the chemical modifications Arg14-Lys15 and (pF)-
Phe4 increased ligand affinity/potency. Peptides with the normal Phe1-Gly2 peptide bond behaved
as full agonists, and those with the Phe1\ube(CH2NH)Gly2 modification behaved as partial
agonists, while those with the Nphe1 modification behaved as partial agonists or pure
antagonists depending on the presence or absence of the (pF)Phe4 modification, respectively.
The full agonist [(pF)Phe4,Arg14,Lys15]N/OFQ-NH2, the partial agonist [Phe1\ube(CH2NH)-
Gly2,(pF)Phe4,Arg14,Lys15]N/OFQ-NH2, and the pure antagonist [Nphe1,Arg14,Lys15]N/OFQ-NH2
represent the most potent peptide ligands for NOP
Structure-activity studies on neuropeptide S - Identification of the amino acid residues crucial for receptor activation
Neuropeptide S (NPS) has been recently recognized as the
endogenous ligand for the previous orphan G-protein-coupled
receptor GPR154, now referred to as the NPS receptor
(NPSR). The NPS-NPSR receptor system regulates important
biological functions such as sleeping/wakening, locomotion,
anxiety, and food intake. To collect information on the mechanisms
of interaction between NPS and its receptor, a classical
structure-activity relationship study was performed.
Human (h) NPS derivatives obtained by Ala and D-scan and
N- and C-terminal truncation were assessed for their ability
to stimulate calcium release in HEK293 cells expressing the
human recombinant NPSR. The results of this study indicate
that (i) the effect of hNPS is mimicked by the fragment hNPS-
(1-10); (ii) Phe2, Arg3, and Asn4 are crucial for biological
activity; (iii) the sequence Thr8-Gly9-Met10 is important for
receptor activation, although with non-stringent chemical
requirements; and (iv) the sequence Val6-Gly7 acts as a hinge
region between the two above-mentioned domains. However,
the stimulatory effect of hNPS given intracerebroventricularly
on mouse locomotor activity was not fully mimicked by
hNPS-(1-10), suggesting that the C-terminal region of the
peptide maintains importance for in vivo activity. In conclusion,
this study identified the amino acid residues of this peptide
most important for receptor activation