Suppression of gonadotropin release and ovulation in animals by inhibitory analogs of luteinizing hormone-releasing hormone.

Abstract

The basic assumption in developing competitive inhibitors of luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH), the structure of which is shown in Figure 1, was that analogs could be designed which could retain the ability to bind to pituitary receptor sites whilst being devoid of gonadotropin-releasing activity. The first indication that this approach was valid came out of work by Vale et al. (1972) who found that removal of histidine from the peptide chain gave a nonapeptide of very low LH-RH activity which was capable of inhibiting the action of LH-RH on cultures of anterior pituitary cells. This inhibition was, however, weak and subsequently could not be demonstrated in vivo in rats (Vilchez-Martinez et al., 1974a). Other inhibitors based on the original decapeptide sequence were shown (Vilchez-Martinez et al., 1974a) to be active in vivo; however, these were also too weak to be of practical value. It became obvious, therefore, that ways must be found to substantially raise the binding affinity of an inhibitor, again without increasing agonistic activity to any great extent.