Structure-activity studies on the corticotropin releasing factor antagonist astressin, leading to a minimal sequence necessary for antagonistic activity.
Corticotropin Releasing Factor (CRF) antagonists are considered promising for treatment of stress-related illnesses such as major depression and anxiety-related disorders. We report here the design, synthesis and biological evaluation of 91 truncated astressin analogues in order to deduce the pharmacophoric amino acid residues. Such truncated peptides may serve as valuable lead structures for the development of new small, non-peptide-based CRF antagonists. N-Terminal truncation of astressin led to active CRF antagonists that are substantially reduced in size and are selectively active at the human CRF receptor type 1 in vitro and in vivo. Subsequently, an alanine scan in combination with further truncated derivatives led to the proposal of a new pharmacophoric model of peptide-based CRF antagonists. It was found that the astressin(27-41)C sequence is the shortest active CRF antagonist. The first eight N-terminal amino acid residues were found to be an important structural determinant and were replaceable by alanine residues, thus enhancing the alpha-helical propensity. A covalent structural constraint is of utmost importance for the preorganization of the C-terminal amino acid residues. The C-terminal heptapeptide sequence, however, was found to be crucial for the antagonistic activity, since substitution or deletion of any residue led to inactive compounds.
Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Utrecht University, P. O. Box 80082, 3508 TB Utrecht, The Netherlands.
Dirk T S
DT
Rijkers
John A W
JA
Kruijtzer
Marja
M
van Oostenbrugge
Eric
E
Ronken
Jack A J
JA
den Hartog
Rob M J
RM
Liskamp
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D013315:Stress, Psychological / Q000188:drug therapy; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; C104416:astressin; D003346:Corticotropin-Releasing Hormone