Synthesis of acyclic and dehydroaspartic acid analogues of Ac-Asp-Glu-OH and their inhibition of rat brain N-acetylated alpha-linked acidic dipeptidase (NAALA dipeptidase).
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 greater than 40 microM), while 2, 3, and 7 with Ki values ranging from 3.2-8.5 microM 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 microM, 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 degrees.
Department of Medicinal Chemistry, College of Pharmacy, Medical School, University of Minnesota, Minneapolis 55455.
N
N
Subasinghe
M
M
Schulte
M Y
MY
Chan
R J
RJ
Roon
J F
JF
Koerner
R L
RL
Johnson
D000818:Animals; D001921:Brain / Q000201:enzymology*; D002462:Cell Membrane / Q000201:enzymology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004150:Dipeptidases / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II; D051381:Rats; D013329:Structure-Activity Relationship
D004151:Dipeptides; C027172:isospaglumic acid; D004150:Dipeptidases; D043425:Glutamate Carboxypeptidase II