Conformationally restrained cyclic peptides as antagonists of luteinizing hormone-releasing hormone.
Using minimum energy calculations and molecular dynamics techniques the preferred conformational states of LHRH and its analogues have been reported to involve a modified beta-bend between residues 5 to 8. Based on some of these models cyclic peptide analogues of LHRH antagonists were synthesised using solid phase peptide synthesis methodology. The analogues were tested for their ability to inhibit ovulation in normal cycling rats. Some analogues were also tested in receptor binding and in vitro LH release assays. The most potent cyclic peptide analogue, Ac-D-Phe(p-C1)-D-Phe(p-C1)-D-Trp-Ser-Glu-D-Arg-Leu-Lys-Pro-D-Ala-NH2 (V), had an ED50 value of 91.9 micrograms/kg in the inhibition of ovulation test. The corresponding linear peptide (IV) was about three times less potent. Analogues with smaller or larger ring sizes or with modifications within the ring were also prepared but these were either less potent or inactive, up to a dose of 1000 micrograms/kg, in inhibiting ovulation in normal cycling rats.
Dutta
A S
AS
ICI Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, England.
Gormley
J J
JJ
McLachlan
P F
PF
Woodburn
J R
JR
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007986:Luteinizing Hormone / Q000378:metabolism; D008969:Molecular Sequence Data; D010060:Ovulation / Q000187:drug effects; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D011966:Receptors, LHRH / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D010456:Peptides, Cyclic; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone