Chapter 18. Gonadotropin Releasing Hormone Antagonists

Abstract

Publisher Summary Till date, more than 3000 analogs of gonadotropin releasing hormone (GnRH) have been prepared in the search for receptor agonist and antagonist drugs related to the structure of this important neuropeptide hormone. In the recent past, this effort has concentrated on the GnRH antagonists with an emphasis on improving the selectivity and duration of action. Both GnRH agonists and antagonists have found utility in treatments where a reversible suppression of the pituitary–gonadal axis is desired. GnRH agonists and antagonists have also been utilized in various assisted fertilization techniques and have been investigated as a potential contraceptive in both men and women. Although they exert discrete biochemical effects, both GnRH agonists and antagonists act to lower the circulating levels of follicle-stimulating hormone (FSH), leutenizing hormone (LH) and, as a consequence of the latter, the gonadal hormones testosterone and estradiol. Prolonged stimulation of the GnRH receptor, with GnRH agonists, results in receptor down-regulation and eventual desensitization of the pituitary, whereas GnRH antagonists act by nonproductive receptor occupation. GnRH agonists typically require 10-14 days to elicit their intended pharmacological outcome. These antagonists have the advantage of immediate pituitary response without the sometimes symptom-exacerbating hormone flare. Toward the de novo design of improved antagonist structures, a computational study of likely drug conformations has been conducted. Energy calculations, using the empirical conformational energy program for peptides (ECEPP) force field has been performed on GnRH, and several agonist and antagonist structures. GnRH agonists are predicted to have a conformation very close to that of the native hormone where it is proposed that a “surface” in the shape of a specifically defined polygon. This chapter discusses the recent progress in the area of GnRH antagonist design.