Inhibition of Bovine Brain Nitric-Oxide Synthase by α-Amino and α-Carboxyl Derivatives of NG-Allyl-L-Arginine
✍ Scribed by J.G. Robertson; M.S. Bernatowicz; A.M. Dhalla; B.B. Muhoberac; J. Yanchunas; G.R. Matsueda; J.J. Villafranca
- Publisher
- Elsevier Science
- Year
- 1995
- Tongue
- English
- Weight
- 426 KB
- Volume
- 23
- Category
- Article
- ISSN
- 0045-2068
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✦ Synopsis
Three derivatives of the mechanism-based inhibitor (N^{\mathrm{G}})-allyl-L-arginine, designed to eliminate the effect of charge on the (\alpha)-functional groups, were synthesized and tested as inhibitors of purified bovine brain nitric oxide synthase. The inhibitory properties of (N^{\mathrm{G}})-allyl-1-arginine, (N^{\mathrm{G}})-allyl-L-arginine methyl ester, (N^{\mathrm{a}})-acetyl- (N^{\mathrm{G}})-allyl-L-arginine, and (N^{\alpha^{\mathrm{a}}})-acetyl- (N^{\mathrm{G}}) allyl-L-arginine methyl ester were determined in steady-state kinetic ass zys. The (K_{i} \mathrm{~s}) of the four compounds were (7 \pm 1,11 \pm 1,147 \pm 13), and (480 \pm 45 \mu \mathrm{M}), respectively. These results demonstrate that conversion of the (\alpha)-carboxyl group of (N^{\mathrm{G}})-allyl-L-arginine to a methyl ester had only a small effect on its inhibitory properties, whereas acetylation of the (\alpha)-amino group increased the (K_{i}) by more than an order of magnitude. Modification of both the (\alpha)-amino and (\alpha)-carboxyl groups increased the (K_{i}) more dramatically from 7 to (480 \mu \mathrm{M}). Derivatization of the (\alpha)-amino and (\alpha)-carboxyl groups of (N^{\mathrm{G}})-allyl-L-arginine would not be expected to alter the chemistry of inactivation by the (N^{\mathrm{G}})-allyl guanidine moiety, and therifore the increased (K_{i} \leqslant) of the derivatives are probably due solely to changes in binding specificity. These data suggest that the arginine binding pocket of brain nitric oxide synthase prefers the unmodified (\alpha)-amino group of arginine for binding, but that it can accommodate a modified (\alpha)-carboxylate. Thus, conservative modification at the (\alpha)-carboxyl may represent a starting point for the design and synthesis of other inhibitors targeted at nitric oxide synthaje. 1995 Academic Press, Inc.