ACTH: A SHORT INTRODUCTORY REVIEW *

Adrenocorticotrophic hormone (adrenocorticotropin, corticotropin, ACTH, FIGURE 1 ) carries vital biologic information from the anterior lobe of the pituitary to the adrenal cortex and other parts of the mammalian body. Practical interest in ACTH has been stimulated by its unique and valuable therapeutic properties. The field of medicinal application has been considerably broadened by the commercial availability of highly purified, synthetic hormone derivatives, e.g., ACTH1-24-tetracosipeptide.1 It now encompasses the treatment of ailments like pituitary insufficiencies, special forms of arthritis, allergies, multiple sclerosis, acute encephalitis and myelitis, tuberculous meningitis, childhood epilepsies, brain edema, acute polyradiculoneuritis, temporal arteritis, herpes zoster, idiopathic paresis of the nervus facialis, myasthenia gravis, etc. The pharmaceutical chemist strives to develop molecules with still improved properties, especially with simpler applicability, longer duration of action, and less antigenicity. The physiologist, the pharmacologist, and the biologist are intrigued by the possibilities offered by ACTH and numerous analogues and derivatives for investigation into the mechanism of hormone action, the precise roles of cyclic AMP and other mediators, and the validity of modern receptor theory. Biochemists are investigating the biosynthetic paths leading to ACTH; molecular biologists and biophysicists are interested in the oneand threedimensional organization of the hormonal information in the ACTH molecule (which is reminiscent of our written language) and the molecular mechanism of its read-out by receptor mo1ecules.2-16 In this short introduction, I would like to remind the participants of this symposium of some fundamental facts and problems on the molecular level that might be of use during the coming, more specialized discussions. ACTH is a linear nonatriacontapeptide with species diflerences in the COOH-terminal two-thirds of the molecule. The amino acid sequences of ACTH from four mammalian species were elucidated between 1954 and 1961 by the three groups of Bell, Li, and Lerner. In 1972, it was discovered by my former co-workers in Basel that the proposed sequences contained minor errors. The corrected primary structures are shown in TABLE 1 . They are taken from the most recent paper of Riniker,17 which refers to the earlier literature in detail. The four structures are virtually identical, except for changes in positions 31 and 3 3 . Dogfish (Squalus acanthias) ACTHIS is equally long, but differs in 11 positions from the human hormone. The replacements are all conservative of the general biologic and physico-chemical properties.