TY - JOUR
T1 - Rationally designed cyclic analogues of luteinizing hormone-releasing hormone
T2 - Enhanced enzymatic stability and biological properties
AU - Laimou, Despina
AU - Katsila, Theodora
AU - Matsoukas, John
AU - Schally, Andrew
AU - Gkountelias, Kostas
AU - Liapakis, George
AU - Tamvakopoulos, Constantin
AU - Tselios, Theodore
N1 - Funding Information:
Despina Laimou was financially supported by the University of Patras (Karatheodoris Grant) . The authors would like to thank the A.G. Leventis Foundation for funding of the Dr C. Tanvakopoulos' lab in the Biomedical Research Foundation of the Academy of Athens. We would like to thank Dr N Kostomitsopoulos and Mr E Balafas for assistance with the in vivo studies. We thank Dr Norman L. Block (University of Miami) for the advice and assistance in the preparation of this manuscript.
PY - 2012/12
Y1 - 2012/12
N2 - 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.
AB - 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.
KW - Amide linked cyclization
KW - Cyclic peptide analogues
KW - Hormone dependent cancer
KW - Luteinizing hormone-releasing hormone
KW - Medicinal chemistry
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U2 - 10.1016/j.ejmech.2012.09.043
DO - 10.1016/j.ejmech.2012.09.043
M3 - Article
C2 - 23127987
AN - SCOPUS:84868261962
VL - 58
SP - 237
EP - 247
JO - CHIM.THER.
JF - CHIM.THER.
SN - 0223-5234
ER -
