Synthesis, conformational analysis and biological activity of cyclic analogs of the octadecaneuropeptide ODNâ: Design of a potent endozepine antagonist
2001
Leprince, Jér´me | Oulyadi, Hassan | Vaudry, David | Masmoudi, Olfa | Gandolfo, Pierrick | Patte, Christine | Costentin, Jean | Fauchère, JeanâLuc | Davoust, Daniel | Vaudry, Hubert | Tonon, MarieâChristine
The octadecaneuropeptide (ODN; QATVGDVNTDRPGLLDLK) and its Câterminal 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 [dâLeu5]OP analog possesses a weak antagonistic activity. The aim of the present study was to synthesize and characterize cyclic analogs of OP and [dâLeu5]OP. Onâresin homodetic backbone cyclization of OP yielded an analog, cyclo1−8 OP, which was three times more potent and 1.4âtimes more efficacious than OP to increase [Ca2+]i in cultured rat astrocytes. Cyclo1−8 OP also mimicked the effect of both OP and ODN on polyphosphoinositide turnover. Conversely, the cyclo1−8[dâLeu5]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 analogs has been determined by twoâdimensional 1HâNMR and molecular dynamics. Cyclo1−8 OP exhibited a single conformation characterized by a γâturn comprising residues Pro2–Leu4 and a type III β turn encompassing residues Leu5–Lys8. Cyclo1−8[dâLeu5]OP was present as two equimolar conformers resulting from cis/trans isomerization of the Arg–Pro peptide bond. These pharmacological and structural data should prove useful for the rational design of non peptidic ODN analogs.
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