Inhibition of cholinesterases by stereoisomers of Huperzine-A

Technical Report · Thu May 13 00:00:00 EDT 1993

OSTI ID:7234931

Saxena, A; Qian, N; Kovach, I M; Ashani, Y; Kozikowski, A P

Huperzine-A, a potential drug for the treatment of Alzheimer's disease and possible pretreament for nerve agent toxicity, has recently been characterized as a reversible inhibitor of cholinesterases (Ashani et al., BBRC, 184:719-726, 1992). Long-term incubation of purified cholinesterases with Huperzine-A did not show any chemical modification of Huperzine-A. The dissociation constant, K(I), for fetal bovine serum acetylcholinesterase (FBS AChE) was approximately 20 nM, for Torpedo AChE was 215 nM, and for horse serum butyrylcholinesterase (BChE) was 40 micrometers M. Inhibition studies with the two stereoisomers of Huperzine-A have shown that naturally occurring (-)-Huperzine-A inhibited FBS AChE 35-fold more potently than (+)-Huperzine-A, with K(I) values of 6.2 nM and 210 nM, respectively. These results are in agreement with those reported previously using crude preparations of rat cortical AChE (McKinney et al., Eur. J. Pharmacol., 203, 303-305, 1991). (-)-Huperzine-A, on the other hand, was 80-fold more potent than (+)-Huperzine-A in inhibiting Torpedo AChE, with K(I), values of 0.25 micrometers M and 22 micrometer M, respectively. No significant differences in K(I) were observed for the two stereoisomers of Huperzine-A with horse serum BChE, indicating the lack of stereoselectivity of this compound for BChE. Molecular modeling studies involving docking of each of the two stereoisomers of Huperzine-A into the active-site gorge of Torpedo AChE also revealed that (-)-Huperzine-A gave a better fit than (+)-Huperzine-A.

• Research Organization: Walter Reed Army Inst. of Research, Washington, DC (United States). Div. of Biochemistry
• OSTI ID: 7234931
• Report Number(s): AD-P-008855/9/XAB
• Resource Relation: Other Information: This article is from 'Proceedings of the Medical Defense Bioscience Review (1993) Held in Baltimore, Maryland on 10-13 May 1993. Volume 3', AD-A275 669, 1015-1023
• Country of Publication: United States
• Language: English

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