title: Conformational analysis of a highly potent dicyclic gonadotropin-releasing hormone antagonist by nuclear magnetic resonance and molecular dynamics.
abstract: Structural analysis of constrained (monocyclic) analogues of gonadotropin-releasing hormone (GnRH) has led to the development of a model for the receptor-bound conformation of GnRH and to the design of highly potent, dicyclic GnRH antagonists. This is one of the first cases where a dicyclic backbone has been introduced into analogues of a linear peptide hormone with retention of high biological activity. Here we present a conformational analysis of dicyclo(4-10,5-8)[Ac-D-2Nal1-D-pClPhe2-D-Trp3-Asp4+ ++-Glu5-D-Arg6-Leu7-Lys8- Pro9-Dpr10]-NH2 (I), using two-dimensional nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation. Compound I inhibits ovulation in the rat at a dose of 5-10 micrograms (Rivier et al. In Peptides: Chemistry, Structure ad Biology; Rivier, J. E., Marshall, G. R., Eds.; ESCOM: Leiden, The Netherlands, 1990; pp 33-37). The backbone conformation of the 4-10 cycle in this dicyclic compound is very similar to that found previously for a parent monocyclic (4-10) GnRH antagonist (Rizo et al. J. Am. Chem. Soc. 1992, 114, 2852-2859; ibid. 2860-2871), which gives strong support to the hypothesis that GnRH adopts a similar conformation upon binding to its receptor. In this conformation, residues 5-8 form a "beta-hairpin-like" structure that includes two transannular hydrogen bonds and a Type II' beta turn around residues D-Arg6-Leu7. The "tail" of the molecule formed by residues 1-3 is somewhat structured but does not populate a single major conformation. However, the orientation of the tail on the same side of the 4-10 cycle as the 5-8 bridge favors interactions between this bridge and the tail residues. These observations correlate with results obtained previously for the parent monocyclic (4-10) antagonist, and have led to the design of a series of new dicyclic GnRH antagonists with bridges between the tail residues and residues 5 or 8.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas 75235-9041.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bienstock
authors.forename: J
authors.initials: J
authors.lastname: Rizo
authors.forename: S C
authors.initials: SC
authors.lastname: Koerber
authors.forename: J E
authors.initials: JE
authors.lastname: Rivier
authors.forename: A T
authors.initials: AT
authors.lastname: Hagler
authors.forename: L M
authors.initials: LM
authors.lastname: Gierasch
mesh_terms: D000595:Amino Acid Sequence; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D010456:Peptides, Cyclic; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone