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Novel cyclic azo‐bridged analogs of gonadotropin‐releasing hormone
Author(s) -
Fridkin Gil,
Rahimipour Shai,
BenAroya Nurit,
Kapitkovsky Aviva,
DiSegni Susanna,
Rosenberg Masha,
Kustanovich Irina,
Koch Yitzhak,
Gilon Chaim,
Fridkin Mati
Publication year - 2006
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.696
Subject(s) - chemistry , receptor , peptide , cyclic peptide , agonist , residue (chemistry) , stereochemistry , tyrosine , peptide hormone , gonadotropin releasing hormone , biological activity , hormone , biochemistry , luteinizing hormone , in vitro
Abstract Five linear analogs of GnRH containing a p ‐aminophenylalanine (Pap) residue in their sequence and their six corresponding azo‐bridged cyclic derivatives were synthesized. The precyclic peptides were prepared on solid‐support, while azo‐cyclization was performed in solution by diazotization of the p ‐aminophenylalanine residue followed by intramolecular coupling of the formed diazo salt with either tyrosine or histidine side chains present in the sequence. All peptides were examined for their binding ability to the GnRH receptor expressed on rat pituitary membranes and for their LH‐release activity from dispersed rat pituitary cells. Linear analogs 1 i.e [Pap 5 ] GnRH and 3, i.e. [Tyr 3 , Pap 5 ] GnRH, were found to bind to the GnRH receptors only slightly less avidly than native GnRH. Their cyclization, however, led to a marked reduction in the binding capacity, i.e. from IC 50 of 10 −9 M to the 10 −7 M range, and in biopotency, i.e. LH‐release. All other linear and cyclic peptides were found to bind selectively to the GnRH receptor only in the low µ M range. Only peptide 1 was found comparable to native GnRH in respect to LH‐release activity and thus may potentially be a good agonist of the parent peptide. Peptides 1 – 4 , the most potent GnRH receptor binders, were examined for their conformational properties using CD. Cyclic‐azo peptides 2 and 4 were further evaluated by NMR spectroscopy in solution combined with molecular modeling. The structural information obtained explains in part the GnRH‐like biological activity observed. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.