Structure‐antinociceptive activity studies with neurotensin

Abstract

1The antinociceptive effects of synthetic neurotensin (NT), its fragments and analogues administered into the lateral cerebroventricle have been compared in the conscious mouse. 2 Intracerebroventricular (i.c.v.) administration of NT produced a dose-dependent antinociceptive effect in the tail pressure test. 3 The NT fragments and analogues, NT(8-13), NT(8-10), NT(9-13), NT(9-11), NT(8-11) NHEt and NT(9-1 1) NHEt were also effective antinociceptive peptides. 4 The potency of NT(8-13) and the duration of its effects were found to be approximately equal to those of NT. 5 The antinociceptive effects produced by NT, NT(8-13) and NT(9-13) were significantly reversed by the opioid antagonist naloxone but not by thyrotropin releasing hormone. 6 It is concluded that NT(8-13) is required for the full expression of the antinociceptive effects of NT which may be mediated in part through the brain opioid system.

Mimicking of Arginine by Functionalized Nω-Carbamoylated Arginine As a New Broadly Applicable Approach to Labeled Bioactive Peptides: High Affinity Angiotensin, Neuropeptide Y, Neuropeptide FF, and Neurotensin Receptor Ligands As Examples

“…Incorporation of the arginine building blocks 10 and 11 into the parent peptides using Fmoc strategy SPPS yielded the peptide analogues 19, 20,25,26,31,33, and 35 bearing aminofunctionalized carbamoyl residues at the guanidine group of arginine (Figure 3). Remarkably, the synthesis of the EYF derivative 35, which required the subsequent coupling of nine amino acids after the incorporation of 10, was obtained in 34% overall yield.…”

“…Stability of the Peptides in Buffer and under Assay Conditions. The chemical stability of the synthesized N ωcarbamoylated peptide derivatives was assessed for the AngII derivatives 19−21, 23, and 24, the NT(8−13) analogues 25, 27, 29, and 30, and the EYF derivatives 35 and 36 in phosphate buffer (pH 7.0, 21 °C) over periods of 24 or 48 h. All peptides proved to be stable (21,27,Figure 4A;19,20,(23)(24)(25)29,30,35, and 36, Supporting Information, Figures S3−S11). The "carba" analogue of the NT(8−13) derivative 25, containing an acylguanidine instead of the carbamoylguanidine moiety (compound 44, Supporting Information, Figure S16) was cleaved, giving the parent compound NT(8−13) devoid of the N ω -acyl substituent (Supporting Information, Figures S17 and S18).…”

“…Numerous biologically active endogenous or truncated peptides such as angiotensin II (AngII), bombesin, bradykinin, gonadoliberin, vasopressin, neuropeptide FF (NPFF), pancreatic polypeptide, , neurotensin(8–13), and kisspeptin-13, are devoid of lysine and cysteine residues but contain arginine. Moreover, arginine-containing chemically modified peptides such as selective or metabolically stable neurotensin NTS 2 receptor ligands, − NPFF analogues (e.g., d Tyr 1 ,NMePhe 3 ]­NPFF and EYF (Figure B)), , C-terminal neuropeptide Y (NPY) analogues, − integrin binding RGD peptides, − cyclic pentapeptides addressing the CXCR 4 chemokine receptor, , opioid receptor ligands, and peptidic melanocortin receptor ligands − were described.…”

Altered morphine-induced analgesia in neurotensin type 1 receptor null mice

“…In that respect, the neurotensinergic system plays a pivotal role in the non-opioid form of stress-induced analgesia (Seta et al, 2001, Gui et al, 2004, Lafrance et al, 2010. There is, however, existing data indicating that the analgesic actions of NT are dependent on the functional integrity of the brain opioid system (van Wimersma Greidanus et al, 1982, Yaksh et al, 1982, Furuta et al, 1984. Above all, mice rendered tolerant to morphine show an attenuated antinociceptive profile to central NT administration (Luttinger et al, 1983).…”

Neurotensin and Xenin Show Positive Correlations With Perceived Stress, Anxiety, Depressiveness and Eating Disorder Symptoms in Female Obese Patients

“…Besides the anti-hypertensive effect of the peptide, many other effects were discovered ( Blackburn, 1978 ) encompassing a stimulation of gut motility and pancreatic secretion of glucagon and insulin, a reduction of gastric acid secretion and a role as growth factor ( Blackburn et al, 1980 ; Yawata et al, 1984 ; Carraway and Plona, 2006 ; Kalafatakis and Triantafyllou, 2011 ). Central effects of neurotensin are hypothermia, food intake suppression, and opioid-independent analgesia as well as an endogenous antipsychotic activity because of interactions with the dopaminergic system ( Martin et al, 1980 ; Luttinger et al, 1982 ; Furuta et al, 1984 ; Fuxe et al, 1992 ). Furthermore, neurotensin displays regulatory functions in pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) ( Herbison and Theodosis, 1991 , 1992 ).…”