Skip to Main content Skip to Navigation
Journal articles

Structure−Activity Relationships of a Series of Analogues of the Octadecaneuropeptide ODN on Calcium Mobilization in Rat Astrocytes §

Abstract : The octadecaneuropeptide ODN (QATVGDVNTDRPGLLDLK), originally characterized as an endogenous ligand for central-type benzodiazepine receptors, increases intracellular calcium concentration ([Ca2+]i) in rat astroglial cells. A series of ODN analogues was synthesized, and each compound was studied for its ability to induce Ca2+ mobilization in cultured rat astrocytes. Replacement of each amino acid by an L-alanine residue (AlaScan) showed that the N-terminal region of the molecule was relatively tolerant to alanine substitution (2-8, 10), except for the Ala9-substituted analogue (9) which was totally devoid of activity. Pyroglutamization (21) and acetylation (22) of the Gln1 residue reduced the Ca2+ response suggesting that a free N-terminal amine function is required for full activity of ODN. Alanine substitution of the residues in the C-terminal region of the molecule (11-14, 16-18) significantly reduced the biological activity of ODN. In particular, modifications of the Leu15 residue (15, 20) abolished the Ca2+-mobilizing activity. The analogues [Ala9]ODN (9), [Ala15]ODN (15), [D-Thr9]ODN (19), and [D-Leu15]ODN (20) partially antagonized the Ca2+ response evoked by ODN. Most importantly, the octapeptide ODN11-18 (OP, 24) produced a dose-response curve that was superimposable to that obtained with ODN, indicating that the C-terminal region of the molecule possesses full biological activity. Finally, the AlaScan of OP revealed that replacement of the Leu5 residue by Ala (29) or D-Leu (33) totally suppressed the calcium response, confirming the crucial contribution of the Leu15 residue of ODN to the biological activity of the neuropeptide.
Complete list of metadatas

https://hal.archives-ouvertes.fr/hal-01972548
Contributor : Jérôme Leprince <>
Submitted on : Monday, January 7, 2019 - 5:27:47 PM
Last modification on : Tuesday, April 7, 2020 - 3:36:04 PM

Links full text

Identifiers

Collections

Citation

Jérôme Leprince, Pierrick Gandolfo, Jean-Louis Thoumas, Christine Patte, Jean-Luc Fauchère, et al.. Structure−Activity Relationships of a Series of Analogues of the Octadecaneuropeptide ODN on Calcium Mobilization in Rat Astrocytes §. Journal of Medicinal Chemistry, American Chemical Society, 1998, 41 (23), pp.4433-4438. ⟨10.1021/jm980275d⟩. ⟨hal-01972548⟩

Share

Metrics

Record views

36