Challenges and Opportunities of Trapping Ligands

Abstract

Because gonadotropin-releasing hormone (GnRH) analogs constitute an important class of therapeutics for various reproductive and hormone-dependent disorders, many novel compounds have been discovered and studied. Several orally active nonpeptide GnRH antagonists have recently gained increased attention. In the study published in this issue of Molecular Pharmacology, Kohout et al. (p. 238) used smallmolecule TAK-013 (sufugolix; developed previously by Takeda Chemical Industries) as a tool to elucidate the mechanism of its insurmountable antagonism. On the basis of receptor mutagenesis combined with molecular modeling, the authors hypothesized that certain amino acid sequences uniquely present in the human GnRH receptor amino terminus and extracellular loop 2 may form a "trap door" retarding dissociation of TAK-013. Such a trapping mechanism could be both ligand-and receptor species-specific. Although analogous models were previously proposed for other G protein-coupled receptors, the study by Kohout et al. (2007) provides an important advance in the GnRH antagonists field and an illustration of the fact that preclinical studies using animal models with nonhuman receptors may have very limited value in predicting drug efficacy in human disease. There are many examples showing that highaffinity protein, peptide, or nonpeptide agonists or antagonists have also enhanced clinical efficacy. However, there are also numerous studies indicating that very high receptor binding affinity is not a guarantee of drug efficacy and that other factors, including pharmacokinetic profile, ligand-induced receptor desensitization, and "trafficking," are critical in design and development of optimal drugs.Gonadotropin-releasing hormone (GnRH) is a polypeptide produced in specialized neurons of the hypothalamus. GnRH is released in pulses into the hypophyseal portal system, reaches the anterior pituitary, and stimulates synthesis and secretion of two gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). GnRH receptor is a member of G protein-coupled receptor superfamily with seven cell membrane-spanning helices. The human GnRH receptor preferentially binds GnRH I and couples to G q/11 protein in pituitary cells, leading to the stimulation of phospholipase C and calcium mobilization (Hazum and Conn, 1988;Millar, 2005). GnRH I is more potent in the activation of the G q/11 protein in the gonadotrope; however, GnRH II is more potent in the stimulation of apoptosis and antiproliferative effects through activating G i protein-mediated signaling. GnRH binding also causes up-regulation and clustering of GnRH receptors, resulting in their internalization, partial degradation, and recycling. Activation of many GPCR receptors, including GnRH receptor, is likely to be associated with breaking, by a ligand, the intrareceptor interactions that stabilize the receptor in its inactive conformations, creating new inter-and intramolecular contacts, resulting in ligandspecific set of receptor conformations (Zhang et al.,...

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