Dose relationship between GnRH antagonists and pituitary suppression

While the clinical significance of gonadotrophin-releasing hormone (GnRH) agonists is well recognized, the potential use of GnRH antagonists in humans awaits the availability of potent analogues with no untoward side-effects. We have designed, synthesized and tested several hundred linear and cyclic analogues (agonists and antagonists) of GnRH in different rat models; some have high histamine releasing activity and others have poor solubility in aqueous buffers with a pH > 6.0. Furthermore, we have identified analogues exhibiting short (< 12 h), intermediate (12-72 h) and long (> 72 h) duration of action in the rat (50 μg s.c. dose/rat). We have concluded that the basis for such resistance to degradation and elimination must be specific. In order to gain further information on the optimal nature and sterical requirements of side-chains, preliminary experiments were carried out using betidamino acids. Finally, mono- and dicyclic analogues of GnRH with potencies comparable with that of the most potent linear analogues were also obtained. Our approach to the development of such analogues included the use of nuclear magnetic resonance and computational techniques as well as that of state-of-the-art synthetic approaches. We intend to use the information derived from these structure/activity relationship studies to design conformationally-similar peptido-mimetics.