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Comparative Conformational Analysis of CCK‐B Agonist Boc‐Trp‐Phg‐Asp‐(1‐Nal)‐NH 2 and CCK‐B Antagonist Boc‐Trp‐Phg‐Asp‐(1‐Nal)‐N(Me) 2 Using 1 H NMR Spectroscopy and Restrained Molecular Dynamics
Author(s) -
Goudreau Nathalie,
Weng Juan Hui,
Roques Bernard P.
Publication year - 1996
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19963290405
Subject(s) - chemistry , tetrapeptide , stereochemistry , agonist , antagonist , nuclear magnetic resonance spectroscopy , peptide , molecular model , two dimensional nuclear magnetic resonance spectroscopy , receptor , biochemistry
The tetrapeptide Boc‐Trp‐Phg‐Asp‐(1‐Nal)‐NH 2 is a potent CCK‐B agonist. Interestingly, bis‐methylation of the C‐terminal carboxamide group of this compound leads to Boc‐Trp‐Phg‐Asp‐(1‐Nal)‐N(Me) 2 which behaves as a CCK‐B antagonist in electrophysiological studies on hippocampal neurones (Corringer et al., 1993). In order to ascertain whether bismethylation of the terminal carboxamide group has an influence on the conformational preferences of the peptide, we have undertaken a comparative conformational analysis of the two tetrapeptides by the combined use of 2D NMR spectroscopy and restrained molecular dynamics. The solution conformation of the two peptides was examined by 1 H NMR in a d 6 ‐DMSO/H 2 O (80:20) mixture. 1 H‐ 1 H distance constraints, derived from 2D NOESY and ROSEY experiments, were used as inputs for subsequent restrained molecular dynamics simulations. Comparison of the NMR and molecular modeling data indicates different conformational preferences for these two peptides. Interestingly, the aromatic side chains of the CCK‐B antagonist Boc‐Trp‐Phg‐Asp‐(1‐Nal)‐N(Me) 2 in its preferential conformation, overlap their corresponding moieties in the two non peptide CCK‐B antagonists L‐362,260 and LY‐288,513. The differences in conformational behaviour of the studied tetrapeptides could, at least in part, account for their opposite agonist/antagonist profile, a findings which could serve for the design of new conformationally restricted CCK‐B analogs.