title: Rationally designed cyclic analogues of luteinizing hormone-releasing hormone: enhanced enzymatic stability and biological properties.
abstract: 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)[Pro(1), D-Leu(6), BABA(10)] 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)[Pro(1), D-Leu(6), BABA(10)] 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)[Pro(1), D-Leu(6), BABA(10)] LHRH render this analogue a promising platform for future rational drug design studies towards the development of non-peptide LHRH mimetics.
authors.affiliation: Department of Chemistry, University of Patras, GR-26500 Patras, Greece.
authors.forename: Despina
authors.initials: D
authors.lastname: Laimou
authors.forename: Theodora
authors.initials: T
authors.lastname: Katsila
authors.forename: John
authors.initials: J
authors.lastname: Matsoukas
authors.forename: Andrew
authors.initials: A
authors.lastname: Schally
authors.forename: Kostas
authors.initials: K
authors.lastname: Gkountelias
authors.forename: George
authors.initials: G
authors.lastname: Liapakis
authors.forename: Constantin
authors.initials: C
authors.lastname: Tamvakopoulos
authors.forename: Theodore
authors.initials: T
authors.lastname: Tselios
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D002478:Cells, Cultured; D015195:Drug Design; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D055550:Protein Stability; D011966:Receptors, LHRH / Q000819:agonists / Q000037:antagonists & inhibitors
chemical_list: D000577:Amides; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; C062876:cetrorelix