STRUCTURE-ACTIVITY ANALYSIS FOR THE EFFECTS OF GAMMA-MSH ACTH-LIKE PEPTIDES ON CEREBRAL HEMODYNAMICS IN RATS/

In a previous structure-activity analysis we have shown that the gamma -melanocyte-stimulating hormones (gamma-MSHs) and structurally related adrenocorticotropic hormone (ACTH) fragments share an amino-acid sequ ence which is determinant for the effects of these peptides on periphe ral hemodynamics, viz. a presser and a tachycardiac response, in consc ious rats. We now investigated whether these structural features are a lso important for the effects of these peptides on cerebral hemodynami cs in urethane-anesthetized rats. After intracarotid and intravenous a dministration, the 'mother' peptides, Lys-gamma(2)-MSH and gamma(2)-MS H, and, with a 10-fold lower potency, ACTH-(4-10), caused a dose-depen dent presser and tachycardiac response, as well as an increase in extr a- and intracranial blood flow and microcirculatory cerebrocortical bl ood flow. Removal of C-terminal amino acids resulted in gamma-MSH-frag ments which were devoid of effects on peripheral and central hemodynam ics. Fragments of gamma(2)-MSH which were shortened at the N-terminal side (gamma-MSH-(4-12) and gamma-MSH-(5-12)) were less potent than gam ma(2)-MSH, but had an intrinsic activity similar to that of gamma(2)-M SH with respect to the presser and tachycardiac effect. However, the p otency and intrinsic activity of these shortened fragments on intracer ebral hemodynamic parameters were the same as those of gamma(2)-MSH. T his suggests that different mechanisms (e.g., site of action and/or me lanocortin receptor subtype) are involved in the cerebral hemodynamic effects of the melanocortins and in their peripheral hemodynamic effec ts. Surprisingly, removal of an additional residue, His(5), resulting in the fragment gamma-MSH-(6-12), led to full restoration of potency w ith respect to extracranial blood flow, blood pressure and heart rate. Neither the structurally related analog, [Nle(4),D-Phe(7)]alpha-MSH ( NDP-MSH), nor ACTH-(1-24) was able to induce a presser effect or cereb ral hemodynamic effects. In contrast, both compounds had a depressor e ffect. It is concluded that the C-terminal amino acids in the structur e of gamma-MSH/ACTH-like peptides are essential for efficacy for the c entral hemodynamic effects, i.e., the increase in intracerebral (micro circulatory) blood flow. However, in contrast to what holds for the pe ripheral hemodynamic features, the N-terminal sequence has hardly any influence on potency or efficacy. The results with NDP-MSH and ACTH-(1 -24) and the other fragments lead us to postulate that it is not one o f the five known subtypes of melanocortin receptors which mediates the hemodynamic effects of the melanocortins, but an additional, still un identified subtype. A clue for the elucidation of such a receptor migh t be found in the structural features of gamma-MSH-(6-12) that appear to be very important determinants for the effectiveness to alter perip heral and central hemodynamics.