Received for publication May 17, 2007.
Revised May 17, 2007.
Accepted for publication May 23, 2007.

Insurmountable Opportunities of Trapping Ligands (Relates to article by Kohout, et al., Fast Forward 4 April 2007)

Abstract

Since 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. Recently, several orally active non-peptide GnRH antagonists gained increased attention. In the study published in this issue of Molecular Pharmacology Khout et al. used small molecule TAK-013 (developed previously by Takeda Chemical Industries) as a tool to elucidate the mechanism of its insurmountable antagonism. Based on 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 (GPCRs), the study by Khout et al. provide an important advance in the GnRH antagonists field and an illustration of the fact that all preclinical studies using animal models with non-human receptors may have very limited value in predicting drug efficacy in human disease. There are many examples showing that high-affinity protein, peptide or non-peptide 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.

Key words: Gonadotropins, Thyrotropin/TRH, Gs family, Gq/11 family, Receptor synthesis/trafficking, Sequestration/Internalization, Structure-activity relationships and modeling, Mutagenesis/Chimeric approaches, Receptor binding studies, Endocrine cells