Rationally designed cyclic analogues of luteinizing hormone-releasing hormone: Enhanced enzymatic stability and biological properties

Despina Laimou, Theodora Katsila, John Matsoukas, Andrew Schally, Kostas Gkountelias, George Liapakis, Constantin Tamvakopoulos, Theodore Tselios

Research output: Contribution to journalArticle

11 Scopus citations


This article describes the rational design, synthesis and pharmacological properties of amide-linked cyclic analogues of Luteinizing Hormone-Releasing Hormone (LHRH) with substitutions at positions 1 (Pro), 6 (d-Leu/d-Trp), 9 (Aze) and 10 (BABA/Acp). These LHRH analogues fulfil the conformational requirements that are known in the literature (bend in the 5-8 segment) to be essential for receptor recognition and activation. Although, they are characterised by an overall low binding affinity to the LHRH-I receptor, the cyclic analogues that were studied and especially the cyclo(1-10)[Pro1, d-Leu6, BABA10] LHRH, exhibit a profoundly enhanced in vitro and in vivo stability and improved pharmacokinetics in comparison with their linear counterpart and leuprolide. Upon receptor binding, cyclo(1-10)[Pro1, d-Leu6, BABA10] LHRH causes testosterone release in C57/B16 mice (in vivo efficacy) that is comparable to that of leuprolide. Testosterone release is an acutely dose dependent effect that is blocked by the LHRH-I receptor antagonist, cetrorelix. The pharmacokinetic advantages and efficacy of cyclo(1-10)[Pro1, d-Leu6, BABA10] LHRH render this analogue a promising platform for future rational drug design studies towards the development of non-peptide LHRH mimetics.

Original languageEnglish (US)
Pages (from-to)237-247
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
StatePublished - Dec 1 2012



  • Amide linked cyclization
  • Cyclic peptide analogues
  • Hormone dependent cancer
  • Luteinizing hormone-releasing hormone
  • Medicinal chemistry

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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