Synthesis of acyclic and dehydroaspartic acid analogs of Ac-Asp-Glu-OH and their inhibition of rat brain N-acetylated .alpha.-linked acidic dipeptidase (NAALA dipeptidase)

Publisher Website
Google Scholar
Abstract
The following structural and conformationally constrained analogues of Ac-Asp-Glu-OH (1) were synthesized: Ac-Glu-Glu-OH (2), Ac-D-Asp-Glu-OH (3), Ac-Glu-Asp-OH (4), Ac-Asp-Asp-OH (5), Ac-Asp-3-aminohexanedioic acid (6), Ac-3-amino-3-(carboxymethyl)propanoyl-Glu-OH (7), N-succinyl-Glu-OH (8), N-maleyl-Glu-OH (9),N-fumaryl-Glu-OH (10), and Ac-.DELTA.ZAsp-Glu-OH (11). These analogues were evaluated for their ability to inhibit the hydrolysis of Ac-Asp-[3,4-3H]-Glu-OH by n-acetylated .alpha.-linked acidic dipeptidase (NAALA dipeptidase) in order to gain some insight into the structural requirements for the inhibition of this enzyme. Analogues 4-6 and 9 were very weak inhibitors of NAALA dipeptidase (Ki > 40 .mu.M), while 2, 3, and 7 with Ki values ranging from 3.2-8.5 .mu.M showed intermediate inhibitory activity. The most active inhibitors of NAALA dipeptidase were compounds 8, 10, and 11 with Ki values of 0.9, 0.4, and 1.4 .mu.M, respectively. These results suggest that the relative spacing between the side chain carboxyl and the .alpha.-carboxyl group of the C-terminal residue may be important for binding to the active site of the enzyme. They also indicate that the .chi.1 torsional angle for the aspartyl residue is in the vicinity of 0.degree.

This publication has 20 references indexed in Scilit: