Novel cyclic azo-bridged analogs of gonadotropin-releasing hormone

Gil Fridkin, Shai Rahimipour, Nurit Ben-Aroya, Aviva Kapitkovsky, Susanna Di-Segni, Masha Rosenberg, Irina Kustanovich, Yitzhak Koch, Chaim Gilon, Mati Fridkin

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6 Scopus citations


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 azocyclization 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 [Pap5] GnRH and 3, i.e. [Tyr3, Pap5] 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 IC50 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 μM 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.

Original languageEnglish
Pages (from-to)106-115
Number of pages10
JournalJournal of Peptide Science
Issue number2
StatePublished - Feb 2006
Externally publishedYes


  • Azo-cyclization
  • GnRH analogs
  • NMR


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