Structure-activity studies, ACTH

Structure-activity studies on ACTH peptide fragments by Bijlsma et al. (1981b) showed most neurotrophic potency to be in three ACTH-like peptides ACTH 4-10, a trisubstituted analog of ACTH 4-9, Org 2766, and a-MSH. The ACTH 4-10 analog BIM 22015 has similar neurotrophic characteristics (Atella et al., 1992 Strand et al., 1993b). The structures of these peptides are shown in Table 1. The remarkable structural specificity of melanocortins is exemplified in a study which shows that a-MSH, [A-leu, D-Phe ]-a-MSH, de-sacetyl-a-MSH and Org 2766 are equally effective when tested in the foot withdrawal reflex, whereas ACTH 7-16 is without effect and ACTH/MSH... 

Bijlsma, W.A., Jennekens, F.G.I., Schotman, P. and Gispen, W.H. (1981b) Effects of corticotropin (ACTH) on recovery of sensorimotor function in the rat structure-activity study. Eur. J. Pharmacol. 76 13-79. 

Proton NMR studies have led Patel to conclude that no interaction occurs between sequences 1-10 and 11-24 in ACTH, 24 Structural relationship of ACTH to biological activity has been discussed by Toniolo . ... 

Human adrenocorticotrophin (ACTH), a peptide hormone consisting of 39 amino acid residues (Fig. 5.3a) was identified as an important factor of the hypothalamus-pituitary-adrenal system in the 1950s, and numerous studies have been conducted ever since to elucidate its struc-ture, plasma concentrations, structure-activity relationships, degradation products, and synthetic analogues.ACTH was shown to... 

The influence of chain length and side-chain modifications of ACTH-derived peptides on active avoidance behaviour in rats will be discussed. H-Met(02)-Glu-His--Phe-D-Lys-Phe-OH (Org 2766) emerged from these studies as an orally active peptide with an increased potency and selectivity of action. Physico-chemical data (from the literature) on the reference peptide ACTH--(4-10) did not point to a preferred conformation in solution, whereas in the crystalline state an antiparallel 3-pleated sheet structure was found. At the receptor site we suggested an a-helical conformation in which the Phe and Met residues are close together. Additional support for this suggestion came from the behavioural activity of [des-Tyr", Met ]enkephalin and of cyclo--(-Phe-Met-cAhx-), eAhx merely serving as a spacer. 

The relationship between the structure of a series of peptides derived from the adrenocorticotropic hormone ACTH, and the behavioural activity in an active avoidance behaviour test, has been studied over the past 10-20 years. The results obtained were quite different from those in which endocrine activity relationships were studied. From the outcome of a quantitative study on the structure--behavioural activity of the ACTH-related peptides, suggestions about the spatial interactions at the receptor site were made. This receptor-bound conformation differed from those suggested by solution experiments or found in crystal structures. 

In another study, a substance with CRF activity was isolated from sheep hypothalami by means of gel filtration and ion-exchange chromatography [289]. The substance, whose structure remains to be determined, has no pressor or ACTH-like activity and is believed to be a single chemical entity. However, the material was not subjected to countercurrent distribution which may separate the 2 CRF activities and thus the possibility of a second CRF cannot be disregarded. Chan, Schaal and Saffran [290] demonstrated two CRF s in rat median eminence tissue, a large and a small CRF. They suggested that the... 

Studies of the molecular structure of ACTH emphasize the problem involved in isolating and identifying a biologically active polypeptide and illustrate some important concepts concerning structure and function relationships [33]. 

The manifold biological activities displayed by ACTH peptides - activities that Include hormonal as well as extra-adrenal effects - offer the peptide chemist a fruitful field In which to study the relationship between structure and function. Earlier work undertaken In the laboratories of LI, Hofmann, Bolssonnas, and Schwyzer was directed towards the synthesis of active ACTH fragments. These efforts culminated In the successful synthesis of hog-type corticotropin by Schwyzer and Sleber (l) and, more recently, of human corticotropin by a Hungarian group (2). In recent years, however, attention has shifted towards the preparation of modified ACTH peptides, and It has been demonstrated that the natural amino acid sequence of corticotropin peptides can be altered considerably with retention of or even an... 

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