Abstract
We have previously reported the synthesis and biological activity of a newly identified peptide of sequence H–Pro–Pro–Thr–Thr–Thr–Lys–Phe–Ala–Ala–OH called acein that is able to stimulate dopamine release in the brain of rodents in vivo and ex vivo by interacting with angiotensin converting enzyme (ACE). In the present piece of work, we studied the structure–activity relationships of acein using displacement experiments of the labelled ligand [125I]Tyr–Pro–Pro–Thr–Thr–Thr–Lys–Phe–Ala–Ala–OH on guinea pig brain membranes, known to have high-affinity acein binding sites. We determined that the C-terminal pentapeptide H–Thr–Lys–Phe–Ala–Ala–OH is the minimal structure able to interact with high affinity (Ki (inhibitory constant) 13 ± 2 nM) with acein binding sites. Among the analogues of the pentapeptide that were synthesized, the pentapeptide H–Thr–Lys–Tyr–Ala–Ala–OH showed the highest affinity (Ki 3.7 ± 1.0 nM). Accordingly, this pentapeptide was able to stimulate dopamine release from striatal slices taken from the sensorimotor territory of rats.