Synthesis of Acyclic and Dehydroaspartic Acid Analogues of Ac-Asp-Glu-OH and Their Inhibition of Rat Brain N-Acetylated α-Linked Acidic Dipeptidase (NAALA Dipeptidase)

Nalin Subasinghe, Marvin Schulte, Michael Y.M. Chan, Robert J. Roon, James F. Koerner, Rodney L. Johnson

Research output: Contribution to journalArticle

39 Scopus citations

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), iV-maleyl-Glu-OH (9), N-fumaryl-Glu-OH (10), and Ac-ΔzAsp-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 α-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 μM), while 2, 3, and 7 with Kivalues ranging from 3.2-8.5 μM showed intermediate inhibitory activity. The most active inhibitors of NAALA dipeptidase were compounds 8, 10, and 11 with Kivalues of 0.9, 0.4, and 1.4 μM, respectively. These results suggest that the relative spacing between the side chain carboxyl and the α-carboxyl group of the C-terminal residue may be important for binding to the active site of the enzyme. They also indicate that the x1torsional angle for the aspartyl residue is in the vicinity of 0°.

Original languageEnglish (US)
Pages (from-to)2734-2744
Number of pages11
JournalJournal of medicinal chemistry
Volume33
Issue number10
DOIs
StatePublished - Oct 1990

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