Biological Characterization of a Novel, Orally Active Small Molecule Gonadotropin-Releasing Hormone (GnRH) Antagonist Using Castrated and Intact Rats

Anderes, Kenna; Luthin, David R.; Castillo, Rosemary; Kraynov, Eugenia; Castro, Mary Ames; Nared-Hood, Karen; Gregory, Margaret L.; Pathak, V. P.; Christie, Lance C.; Paderes, Genevieve; Vazir, Haresh; Ye, Qiang; Anderson, Mark; May, Jeanine

doi:10.1124/jpet.102.046656

Cited by 42 publications

(30 citation statements)

References 37 publications

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“…Finally, FD-1 was tested, which belongs to a different class of nonpeptidic antagonists (Table 1). FD-1 had a K i value of 4.9 Ϯ 1 nM, which was comparable with the affinity reported for an analog of this compound, CMPD-1 (K i ϭ 6.0 Ϯ 0.8 nM) (Anderes et al, 2003).…”

Section: The Human Gnrh Receptor Has Two Distinct Allosteric Sites 1813supporting

confidence: 65%

“…CMPD-1 has recently been shown to be an allosteric inhibitor for the GnRH receptor too (Sullivan et al, 2006). Previously, that same compound (named Furan-1 or CMPD-1) had been demonstrated to be a potent nonpeptidic antagonist (Anderes et al, 2003), whereas its allosteric effects occur at higher concentrations. FD-1 and CMPD-1 belong to the same class of nonpeptidic antagonists with only some small structural differences (Fig.…”

Section: The Human Gnrh Receptor Has Two Distinct Allosteric Sites 1813mentioning

confidence: 99%

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Amiloride Derivatives and a Nonpeptidic Antagonist Bind at Two Distinct Allosteric Sites in the Human Gonadotropin-Releasing Hormone Receptor

Heitman

Ye²,

Oosterom³

et al. 2008

Mol Pharmacol

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The interest in the allosteric modulation of G protein-coupled receptors has grown during the past decade. It has been shown that ligands acting at allosteric sites present in these important drug targets have the ability to modulate receptor conformations and fine-tune pharmacological responses to the orthosteric ligand. In the present study, allosteric modulation of the human gonadotropin-releasing hormone (GnRH) receptor by amiloride analogs [e.g., 5-(N,N-hexamethylene)amiloride (HMA)] and a nonpeptide antagonistic furan derivative (FD-1) was studied. First, the compounds' ability to influence the dissociation of a radiolabeled peptide agonist ( I-triptorelin, revealing their allosteric inhibitory characteristics. The simultaneous addition of HMA and FD-1 resulted in an additive effect on the dissociation rate. Second, in a functional assay, it was shown that HMA was a noncompetitive antagonist and that FD-1 had both competitive and noncompetitive antagonistic properties. Equilibrium displacement studies showed that the inhibition of 125 I-triptorelin binding by FD-1 was not affected by HMA. Furthermore, the potency of HMA to increase radioligand dissociation was not affected by the presence of FD-1. Simulation of the data obtained in the latter experiment also indicated neutral cooperativity between the binding of HMA and FD-1. Taken together, these results demonstrate that HMA and FD-1 are allosteric inhibitors that bind at two distinct, noncooperative, allosteric sites. This presence of a second allosteric site may provide yet another opportunity for the discovery of new ligands for the human GnRH receptor.The gonadotropin-releasing hormone (GnRH) receptor belongs to the rhodopsin-like subfamily (class A) of G proteincoupled receptors (GPCRs) (Millar et al., 2004). Activation of the GnRH receptor results in the biosynthesis and secretion of the gonadotropins luteinizing hormone and follicle-stimulating hormone. The gonadotropins bind to their respective receptors on the gonadal cells, which stimulates germ cell development and hormone secretion in the ovaries (Rhoades and Pflanzer, 1996). GnRH, also named luteinizing hormonereleasing hormone, is a linear hypothalamic decapeptide ( Fig. 1) and was first isolated and characterized by Schally et al. (1971). Several peptidic agonists and antagonists for the GnRH receptor have been approved for the treatment of a variety of sex-hormone-dependent diseases, such as prostate and breast cancer and endometriosis (Conn and Crowley, 1994;Kiesel et al., 2002). Superagonists, a somewhat ambiguous term for continually administered peptidic agonists, are used to desensitize and down-regulate the GnRH receptor, resulting in gonadal suppression. Such use of agonists, however, produces an initial hormonal "flare," resulting in a temporary activation of the pituitary, which can be prevented by giving peptidic antagonists instead. However, peptidic compounds often need to be administered by parenteral (subcutaneous or intramuscular) injection (Kiesel et al., 2002). The...

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Section: The Human Gnrh Receptor Has Two Distinct Allosteric Sites 1813supporting

confidence: 65%

Section: The Human Gnrh Receptor Has Two Distinct Allosteric Sites 1813mentioning

confidence: 99%

Amiloride Derivatives and a Nonpeptidic Antagonist Bind at Two Distinct Allosteric Sites in the Human Gonadotropin-Releasing Hormone Receptor

Heitman

Ye²,

Oosterom³

et al. 2008

Mol Pharmacol

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“…Based on the previous SAR studies, 46,47 compound 32 was developed, which contains a 2,4,6-trimethoxyphenyl group at the amide bond. 48 Anderes and co-workers evaluated 32 for its bioavailability and activity in vivo. Compound 32 had a high affinity for the human GnRH receptor (K i ¼ 6.0 nM) and showed functional antagonism in vitro.…”

Section: G Furamide Derivativesmentioning

confidence: 99%

G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

Heitman

IJzerman

2008

Medicinal Research Reviews

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The hypothalamic-pituitary-gonadal (HPG) axis, important in reproduction and sex hormone-dependent diseases, is regulated by a number of G protein-coupled receptors. The recently "deorphanized" GPR54 receptor activated by the peptide metastin is thought to be the key regulator of the axis, mainly by releasing gonadotropin-releasing hormone (GnRH) from the hypothalamus. The latter decapeptide, through the activation of the GnRH receptor in the anterior pituitary, causes the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently activate their respective receptors on the gonadotrope cells. In this review we will discuss the small molecule agonists and antagonists that are currently being developed to intervene with the action of these four receptors. For GnRH receptors, 14 different chemical classes of non-peptidic antagonists have been reported, while for the LH receptor three classes of agonists have been described. Both agonists and antagonists have been introduced for the FSH receptor. Recently, the first non-peptidic agonist for GPR54 was reported.

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“…The GnRH antagonist CMPD1 (or AG-045572) [46] is a compound developed for oral bioavailability that, when administered to intact male rats at a single dose of 100 mg/ kg, maintained suppression of testosterone in the castrate range for 24 hours [47]. Unfortunately, work on this compound has been suspended and Pfizer/Agouron is waiting to see if there is a significant market for an orally available GnRH antagonist.…”

Section: Non-peptide Gnrh Antagonistsmentioning

confidence: 99%

Gonadotropin-releasing hormone antagonists

Herbst¹

2003

Current Opinion in Pharmacology

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Biological Characterization of a Novel, Orally Active Small Molecule Gonadotropin-Releasing Hormone (GnRH) Antagonist Using Castrated and Intact Rats

Cited by 42 publications

References 37 publications

Amiloride Derivatives and a Nonpeptidic Antagonist Bind at Two Distinct Allosteric Sites in the Human Gonadotropin-Releasing Hormone Receptor

Amiloride Derivatives and a Nonpeptidic Antagonist Bind at Two Distinct Allosteric Sites in the Human Gonadotropin-Releasing Hormone Receptor

G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

Gonadotropin-releasing hormone antagonists

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