TAILIEUCHUNG - Báo cáo Y học: Synthesis, conformational analysis and biological activity of cyclic analogs of the octadecaneuropeptide ODN Design of a potent endozepine antagonist

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 ([Ca21]i) in cultured rat astrocytes through activation of a metabotropic receptor positively coupled to phospholipase C. It has also been found that the [D -Leu5]OP analog possesses a weak antagonistic activity. The aim of the present study was to synthesize and characterize cyclic analogs of OP and [D -Leu5]OP. On-resin homodetic backbone cyclization of OP yielded an analog, cyclo128 OP, which was three times more potent and more efficacious than OP to increase [Ca21]i in. | Eur. J. Biochem. 268 6045-6057 2001 FEBS 2001 Synthesis conformational analysis and biological activity of cyclic analogs of the octadecaneuropeptide ODN Design of a potent endozepine antagonist Jerome Lenrince 1 Hassan Oulvadi2 David Vaudrv1. Olfa Masmoudi1. Pierrick Gandolfo1. Christine Patte1 Jean Costentin3 Jean-Luc Fauchere4 Daniel Davoust2 Hubert Vaudry1 and Marie-Christine Tonon1 1Institut Federatif de Recherches Multidisciplinaires sur les Peptides IFRMP 23 Laboratoire de Neuroendocrinologie Cellulaire et Moleculaire Institut National de la Sante et de la Recherche Medicale Unite 413 CNRS Universite de Rouen Mont-Saint-Aignan France 2IFRMP 23 Laboratoire de Resonance Magnetique Nucleaire Institut de Recherche en Chimie Organique Fine CNRS Unite Mixte de Recherches 6014 Universite de Rouen Mont-Saint-Aignan France 3IFRMP 23 Laboratoire de Neuropsychopharmacologie CNRS Unite Mixte de Recherches 6036 Universite de Rouen Rouen France Institut de Recherches SERVIER Suresnes France 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 Ca2 i in cultured rat astrocytes through activation of a metabotropic receptor positively coupled to phospholipase C. It has also been found that the D-Leu5 OP analog possesses a weak antagonistic activity. The aim of the present study was to synthesize and characterize cyclic analogs of OP and D-Leu5 OP. On-resin homodetic backbone cyclization of OP yielded an analog cyclo128 OP which was three times more potent and more efficacious than OP to increase Ca2 i in cultured rat astrocytes. Cyclo128 OP also mimicked the effect of both OP and ODN on polyphosphoinositide turnover. Conversely the cyclo128 D-Leu5 OP analog was totally devoid of agonistic activity but suppressed the effect of OP and ODN on Ca2 i and phosphoinositide metabolism in astrocytes. The structure of these cyclic .

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