Gonadotropin-releasing hormone analog design. Structure-function studies toward the development of agonists and antagonists: Rationale and perspective

Abstract

On JUNE 24, 1971, Andrew V. Schally announced the determination of the primary structure of porcine GnRH at The Endocrine Society Meeting in San Francisco. This announcement was followed by publications by Matsuo et al. (1, 2) and Baba et al. (3) on the proposed amino acid sequence for porcine GnRH and its synthesis and by Burgus et al. (4) who characterized ovine GnRH and found the sequence to be identical with that of porcine GnRH. The physiological and therapeutic importance attributed to the discovery of the new substance was greatly increased by the prospect of the design of potent and long acting GnRH agonists and antagonists. Since that time more than 2000 analogs of GnRH have been synthesized. The impact of research of GnRH and its analogs on clinical medicine recently led Ziporyn (5) to note, “There’s almost no subspecialty of medicine that will be left untouched by the [research] advances associated with LHRH or its analogs.” It is the intent of this article to provide a historical review of the major, and some minor, aspects of the chemical development of GnRH agonists and antagonists up to the present state of development (July 1, 1985). The synthetic chemical efforts have been devoted largely to increasing the affinity of the peptides to the GnRH receptor and their resistance to degradation or elimination in in vivo systems, characteristics which, for the GnRH analogs, are generally interrelated. © 1986 by The Endocrine Society.