Organic Letters
Letter
hydroxynorketamine and (2S,6S)-hydroxynorketamine in the
treatment of depression, anxiety, anhedonia, suicidal ideation
and post-traumatic stress disorders. C.A.Z., R.M., C.T., and P.M.
have assigned their rights in this patent to the U.S. government
but will share a percentage of any royalties that may be received
by the government. T.G. and P.Z. have assigned their rights in
this patent to the University of Maryland but will share a
percentage of any royalties that may be received by the University
of Maryland.
Table 1. Binding Affinities and Inhibitory Effects of Ketamine
and Its Metabolites against the NMDA Receptor
a
a
a
compd
(+)-MK-801
IC50 (μM)
Ki (μM)
% inhibition at 100 μM
0.00493
0.35
0.00348
0.25
100
91
90
99
68
66
24
85
8
(R,S)-ketamine (1)
(R)-norketamine (2a)
(S)-norketamine (2b)
(R)-DHNK (3a)
0.85
0.6
1.23
0.87
59.7
42.1
(S)-DHNK (3b)
42
29.7
(2R,6R)-HNK (7a)
(2S,6S)-HNK (7b)
(2R,6S)-HNK (4a)
(2S,6R)-HNK (4b)
(2R,5R)-HNK (8a)
(2S,5S)-HNK (8b)
(2R,5S)-HNK (9a)
(2S,5R)-HNK (9b)
(2R,4S)-HNK (10a)
(2S,4R)-HNK (10b)
(2R,4R)-HNK (11a)
(2S,4S)-HNK (11b)
>100
10.4
>100
7.34
ACKNOWLEDGMENTS
■
This work was supported by the NIH intramural research fund.
Receptor binding profiles, IC50, and Ki determinations were
performed by Eurofins Panlabs Discovery Services, Taipei,
Taiwan.
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
24
12
27
10
35
23
34
3
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■
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
Experimental Procedures, characterization data, NMR
spectra, and X-ray crystallographic data (PDF)
X-ray data for all hydroxynorketamines (CIF, CIF, CIF,
AUTHOR INFORMATION
■
Corresponding Author
ORCID
Notes
The authors declare the following competing financial
interest(s): R.M., and C.A.Z. are listed as co-inventors on a
patent for the use of (2R,6R)-hydroxynorketamine, (S)-
dehydronorketamine and other stereoisomeric dehydro and
hydroxylated metabolites of (R,S)-ketamine metabolites in the
treatment of depression and neuropathic pain. They have
assigned their rights in the patent to the U.S. government but will
share a percentage of any royalties that may be received by the
government. C.A.Z., R.M., T.G., P.Z., C.T., and P.M. are listed as
co-inventors on a patent application for the use of (2R,6R)-
D
Org. Lett. XXXX, XXX, XXX−XXX