Synthesis, conformational analysis and biological activity of cyclic analogs of the octadecaneuropeptide ODN

Abstract

The octadecaneuropeptide (ODN; QATVGDVNTDRPG LLDLK) and its C-terminal octapeptide (OP; RPGLLDLK), which exert anxiogenic activity, have been previously shown to increase intracellular calcium concentration ([Ca 21 ] i ) in cultured rat astrocytes through activation of a metabotropic receptor positively coupled to phospholipase C. It has also been found that the [7].The mechanism of action of endozepines is not fully understood. It has been initially proposed that these peptides act as inverse agonists of central-type benzodiazepine receptors [6] thus inhibiting the activity of the GABA Achloride channel complex [8]. Subsequently, endozepines were found to interact with peripheral-type BZ receptors and to stimulate cholesterol transport into mitochondria [9]. More recently, it has been shown that, in rat astrocytes, ODN activates a metabotropic receptor positively coupled to phospholipase C, leading to an increase in cytosolic calcium concentration [10,11]. Structure-activity relationship studies have shown that the C-terminal octapeptide of ODN (OP; ODN 11218 ) is the minimum sequence retaining full calcium-mobilizing activity [12]. The Ala-scan of OP has revealed that replacement of the Leu6 residue suppresses the activity of the peptide. It has also been found that the

The Anorexigenic Action of the Octadecaneuropeptide (ODN) in Goldfish is Mediated Through the MC4R- and Subsequently the CRH Receptor-Signaling Pathways

“…ODN acts as inverse agonists of central-type benzodiazepine receptors, thus inhibiting the activity of GABA A receptors (Guidotti et al 1983;Tonon et al 1989;Costa and Guidotti 1991;Louiset et al 1993;Do Rego et al 2001). ODN can also activate a metabotropic receptor positively coupled to the phospholipase C cascade through a pertussis toxin-sensitive G-protein (Patte et al 1995;Lamacz et al 1996;Gandolfo et al 1997;Leprince et al 2001).…”

Identification of 26RFa, a hypothalamic neuropeptide of the RFamide peptide family with orexigenic activity

“…Human 26RFa (TSGPLGNLAEELNGYS-RKKGGFSFRF-NH 2 ), rat 26RFa (ASGPLGTLAEELSSYSR-RKGGFSFRF-NH 2 ), and frog R-RFa (SLKPAANLPLRF-NH 2 ) were synthesized (0.1-mmol scale) by the solid phase methodology on a Rink amide 4-methylbenzhydrylamine resin (Biochem, Meudon, France) by using a 433A Applied Biosystems peptide synthesizer and the standard fluorenylmethoxycarbonyl (Fmoc) procedure as described (24). The synthetic peptides were purified by reverse-phase HPLC on a 2.2 ϫ 25-cm Vydac 218TP1022 C 18 column (Alltech, Templemars, France) by using a linear gradient (10-50% over 50 min) of acetonitrile͞ trifluoroacetic acid (99.9:0.1, vol͞vol) at a flow rate of 10 ml͞min.…”

Octadecaneuropeptide ODN prevents hydrogen peroxide-induced oxidative damage of biomolecules in cultured rat astrocytes

“…Indeed, the inhibitory effects of ODN on H 2 O 2 -evoked ROS accumulation and LDH leakage were both suppressed by the selective metabotropic ODN receptor antagonist cDOP, but were not affected by the specific CBR antagonist flumazenil. Previous studies have shown that the metabotropic ODN receptor is coupled to either PLC/PKC [28] or AC/PKA signaling pathways [24]. Here, we observed that the AC inhibitor ddA blocked the inhibitory effect of ODN on H 2 O 2 -induced intracellular ROS accumulation, while the PLC inhibitor U73122 had no effect.…”

“…Clonazepam and flumazenil were generous gifts from Hoffmann-La Roche (Basle, Switzerland). Rat ODN (QATVGDVNTDRPGLLDLK), the C-terminal octapeptide fragment (RPGLLDLK, OP) and its cyclic analog (cyclo 1-8 [DLeu 5 ]OP, cDOP) were synthesized by using the standard Fmoc procedure, as previously described [28]. All other reagents were of A grade purity.…”

“…DBI and its processing products are collectively designated by the term endozepines [39]. ODN acts through two types of receptors, the central-type benzodiazepine receptors (CBR) associated with the GABA A receptor complex [6,18] and a metabotropic receptor positively coupled to either phospholipase C (PLC) [28] or adenylyl cyclase (AC) [24]. The primary structure of ODN has been strongly conserved during evolution [10,39], suggesting that this peptide plays important biological functions.…”