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)[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 language | English |
|---|---|
| Pages (from-to) | 237-247 |
| Number of pages | 11 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 58 |
| DOIs | |
| State | Published - Dec 1 2012 |
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Keywords
- Amide linked cyclization
- Cyclic peptide analogues
- Hormone dependent cancer
- Luteinizing hormone-releasing hormone
- Medicinal chemistry
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry
- Pharmacology
Cite this
Rationally designed cyclic analogues of luteinizing hormone-releasing hormone : Enhanced enzymatic stability and biological properties. / Laimou, Despina; Katsila, Theodora; Matsoukas, John; Schally, Andrew V; Gkountelias, Kostas; Liapakis, George; Tamvakopoulos, Constantin; Tselios, Theodore.
In: European Journal of Medicinal Chemistry, Vol. 58, 01.12.2012, p. 237-247.Research output: Contribution to journal › Article
}
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 V
AU - Gkountelias, Kostas
AU - Liapakis, George
AU - Tamvakopoulos, Constantin
AU - Tselios, Theodore
PY - 2012/12/1
Y1 - 2012/12/1
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
UR - http://www.scopus.com/inward/record.url?scp=84868261962&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84868261962&partnerID=8YFLogxK
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 - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -