Luteinizing hormone-releasing hormone. Antiovulatory activity of analogs substituted in positions 2 and 6

Beattie, Craig W.; Corbin, Alan; Foell, Theodore; Garsky, Victor M.; McKinley, W. A.; Rees, R. W.; Sarantakis, Dimitri; Yardley, J. P.

doi:10.1021/jm00246a016

Cited by 33 publications

(13 citation statements)

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“…In addition to the ability of such analogs to stimulate or inhibit LH and FSH release, both antagonist and superagonist analogs have potent antigonadal and antifertility actions, suggesting that these compounds may be useful as reversible contraceptive agents (11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

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confidence: 99%

Receptor-Binding Affinity of Gonadotropin-Releasing Hormone Analogs: Analysis by Radioligand-Receptor Assay

1980

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A recently developed radioligand-receptor assay for pituitary gonadotropin-releasing hormone (GnRH) receptors, employing a radioiodinated superagonist analog as the ligand, was used to analyze the receptor-binding properties of several GnRH analogs. This receptor assay is specific for GnRH and related peptides with agonist or antagonist activity. All superagonist analogs had equilibrium association constants (Ka) between 4-and 8-fold greater than that of the natural GnRH decapeptide (Ka = 6.6 x 10 8 M~'). Conversely, weak agonists and inactive analogs were bound with affinities 0.003-0.05 times that of GnRH. Weak antagonists, such as [D-Phe 2 ]GnRH and [DPhe 2 , D-Phe 6 ]GnRH, had lower binding constants, while the most potent antagonist, [D-pGlu 1 , D-Phe 2 , D-Trp 3 ' 6 ]GnRH, exhibited 8-fold higher affinity than GnRH for pituitary receptors. There was a general positive correlation between receptor-binding affinity and relative biological activity, whether agonist or antagonist, for the several GnRH analogs tested. However, the observed increases in receptor affinity (4-to 8-fold) did not account for the 30-to 100-fold greater LH-releasing activity of the superagonists. The relatively high bioactivity of such analogs in comparison to their binding constants is attributable to their increased resistance to degradation in addition to their increased binding affinity. Comparison of receptor binding data with structural features of the GnRH analogs revealed that the three Nterminal amino acids are critical for receptor recognition, while the C-terminal des-Gly 10 ethylamide modification does not enhance binding affinity. The radioligand assay provides a rapid and reliable method for evaluating the contribution of receptorbinding affinity to the agonist or antagonist actions of new GnRH analogs. This procedure also permits systematic determination of the structural requirements for GnRH receptor recognition. (Endocrinology 106: 1154, 1980)

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confidence: 99%

Receptor-Binding Affinity of Gonadotropin-Releasing Hormone Analogs: Analysis by Radioligand-Receptor Assay

1980

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“…Additionally, GnRH antagonists were tested in vivo in the castrated male rat for duration of action. The assay was originally reported by Corbin and Beattie26 and subsequently extensively modified by us27 (Figure 2). In short, test compounds were injected subcutaneously (sc) to castrated male rats at a standard dose of 50 μg/rat.…”

Section: Methodsmentioning

confidence: 99%

Novel gonadotropin‐releasing hormone antagonists with substitutions at position 5

Samant

Hong²,

Croston³

et al. 2004

Biopolymers

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Gonadotropin-releasing hormone (GnRH) antagonists with high potency and improved duration of action are needed for potential clinical applications. We synthesized four new antagonists (2-5) of GnRH homologues to Azaline B (1), with a common core sequence of [Aph(X)5, D-Aph(Cbm)6]Azaline B. In these analogs, (X) contains hydrophobic aromatic moieties (like homoveratoyl in 2, homovanillyl in 3, 2,5-dimethoxyphenylacetyl in 4, and 3,5-dimethoxyphenylacetyl in 5) designed to improve the duration of action over that of Azaline B. These analogs were tested in vitro for their ability to antagonize the GnRH receptor and in vivo for duration of action in a castrated male rat assay. Analogs 2, 4, and 5 were potent in vitro, but were found to be short acting in vivo. However, analog 3 [Aph(Hvn)5,D-Aph(Cbm)6]Azaline B is a potent human GnRH receptor antagonist in vitro (IC50 1.47 nM) and exhibits a longer duration of action than azaline B.

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“…For example, replacing D-Phe by D-pClPhe in [D-Phe 2 , D-Ala 6 ]-LHRH decreased antiovulatory activity [7], but the same change in the sequence [N-Ac-Thr 1 . D-Phe 2 .D-Trp 3 > 6 ]-LHRH increased inhibitory activity in vitro as well as antiovulatory activity [6,8].…”

Section: Introductionmentioning

confidence: 99%

Antiovulatory Potency and Conformation of an Antagonist of the Luteinizing Hormone-Releasing Hormone Having Six D-Amino Acids

Folkers

Bowers

Momany

et al. 1982

Zeitschrift Für Naturforschung B

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Abstract [N-Ac-Thr 1 ,D-Phe 2,D-Trp 3,6]-LHRH was the model antagonist of LHRH, which was the basis for tho design, synthesis and bioassay of seven peptides having four, five and six D-amino acids, which resulted from three single, three double, and one triple introductions of D-amino acids in positions 4, 5 and 8 of the model. Only the analog with six D-amino acids, [N-Ac-Thr 1,D-Phe 2 ,D-Trp 3,D-Ser 4, D-Tyr 5 ,D-Trp 6 ,D-Arg 8]-LHRH, had antiovulatory activity which was higher than that of the model antagonist, i.e., 70% antiovulatory activity at 25 μg/rat compared with 50% activity at 50 μg/rat, respectively. Empirical energy calculations gave a conformational structure for [N-Ac-Thr 1,D-Phe 2,D-Trp 3, D-Ser 4,D-Tyr 5,D-Arg 6,D-Arg 8]-LHRH which is similar to that calculated for previous potent antagonists. These results are a basis of new designs of antagonists having D-sub-stituents in up to ten positions toward effective inhibitors of ovulation by the parenteral and oral routes of administration.

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Luteinizing hormone-releasing hormone. Antiovulatory activity of analogs substituted in positions 2 and 6

Cited by 33 publications

References 1 publication

Receptor-Binding Affinity of Gonadotropin-Releasing Hormone Analogs: Analysis by Radioligand-Receptor Assay

Receptor-Binding Affinity of Gonadotropin-Releasing Hormone Analogs: Analysis by Radioligand-Receptor Assay

Novel gonadotropin‐releasing hormone antagonists with substitutions at position 5

Antiovulatory Potency and Conformation of an Antagonist of the Luteinizing Hormone-Releasing Hormone Having Six D-Amino Acids

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