Peptide ACTH-derived, structure-activity

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. 

For activity of ACTH-derived peptides at the receptor for pole-jumping activity, the basic requirement seems to be the presence of a Phe and Met residue in close proximity. It is interesting to see that Phe and Met are close together in an a-helical structure in ACTH peptides (and as intra-chain neighbours in Met-enkephalin) and in the crystalline state in ACTH-(4-10) as a 3-pleated sheet and in ACTH-(4-7) in the form of a horseshoe this close proximity is in line with the results of a Free-Wilson type of analysis. 

Structure-Behavioral Activity Relationships of Peptides Derived from ACTH... 

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. 

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