Design, synthesis, and evaluation of a long-acting, potent analogue of gonadotropin-releasing hormone.

Abstract

The design, synthesis, and biological evaluation of a gonadotropin-releasing hormone (GnRH) agonist, [D-Lys(6)(1,3,8-trihydroxy-6-carboxyanthraquinone)]GnRH ([D-Lys(6)(Emo)]GnRH), is described. Synthesis of this analogue was carried out in a homogeneous solution as well as on a polymer support. [D-Lys(6)(Emo)]GnRH was found to bind to rat pituitary GnRH receptors (IC(50) = 0.25 nM), to induce luteinizing hormone (LH) release (ED(50) = 27 pM), and to be devoid of any toxicity. This analogue also proved to be a very potent agonist in vivo and exhibited a prolonged bioactivity. Six hours after its administration to rats, LH levels were substantially higher than those of rats treated with a 10-fold higher dose of the parent peptide. Moreover, chronic treatment of adult male rats with [D-Lys(6)(Emo)]GnRH (0.1 nmol/rat) for one week resulted in a further decrease of the weight of the testes and prostate as compared to those of rats that were treated with a higher dose of [D-Lys(6)]GnRH (1 nmol/rat). The prolonged activity of [D-Lys(6)(Emo)]GnRH may be attributed to its emodic acid moiety, which enhances the binding affinity of the analogue to human serum albumin. Indeed, we found that emodic acid binds to human serum albumin almost completely at the examined range of concentrations.