Journal of Medicinal Chemistry
Brief Article
A = water plus 0.05% TFA (v/v), B = acetonitrile plus 0.05% TFA (v/
v). Gradient: 0.0−4.0 min 90% A, 4.0−29.0 min from 90% A to 0% A,
29.0−31.0 min 0% A, 31.0−31.5 min from 0% A to 90% A, 31.5−40.0
min 90% A. Flow rate: 1 mL/min. UV detection: 210 nm. The purity
of all compounds was ≥98%.
Receptor Binding Studies. The affinities of 17−26 toward the
PCP binding site of the NMDA receptor were determined in
competition experiments using [3H]-(+)-MK-801 as radioligand and
membrane preparations from pig brain cortex as receptor material.
The σ1 receptor binding assay was carried out with homogenates of
guinea pig brains as receptor material and [3H]-(+)-pentazocine as
radioligand. These experiments had been optimized with respect to
previously reported binding studies.16
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ASSOCIATED CONTENT
* Supporting Information
■
S
Purity data of the primary amines 17−21 and the benzyl
amines 22−26; synthesis of compounds 12−26 and data
thereof; materials and procedures for the NMDA, σ1, and σ2
receptor binding assays and σ2 receptor affinities; HPLC
methods; ee of (S)-10 and (R)-10; ee of the bis-4-
bromobenzoates of (S)-11 and (R)-11; CD-/UV-spectra of
the bis-4-bromobenzoates of (S)-11 and (R)-11; de of (R,S)-
12, (S,S)-14 and (S,S)-15; 1H NMR and NOE spectra of (R,S)-
12, (S,S)-13, (S,S)-14, (S,S)-15, and (S,S)-16. This material is
(15) Thurkauf, A.; Mattson, M. V.; Richardson, S.; Mirsadeghi, S.;
Ornstein, P. L.; Harrison, E. A., Jr.; Rice, K. C.; Jacobson, A. E.; Monn,
J. A. Analogues of the dioxolanes dexoxadrol and etoxadrol as potential
phencyclidine-like agents. Synthesis and structure−activity relation-
ships. J. Med. Chem. 1992, 35, 1323−1329.
AUTHOR INFORMATION
Corresponding Author
*Phone: +49 251 83 33311, Fax: +49 251 83 32144, E mail:
(16) Utech, T.; Kohler, J.; Wunsch, B. Synthesis of 4-(aminoalkyl)
̈
̈
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substituted 1,3-dioxanes as potent NMDA and σ receptor antagonists.
Eur. J. Med. Chem. 2011, 46, 2157−2169.
(17) Aepkers, M.; Wunsch, B. Structure−affinity relationship studies
̈
of non-competitive NMDA receptor antagonists derived from
Notes
dexoxadrol and etoxadrol. Bioorg. Med. Chem. 2005, 13, 6836−6849.
The authors declare no competing financial interest.
(18) Kohler, J.; Wunsch, B. Lipase catalyzed enantioselective
̈
̈
desymmetrization of a prochiral pentane-1,3,5-triol derivative.
Tetrahedron: Asymmetry 2006, 17, 3091−3099.
ABBREVIATIONS USED
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(19) Kohler, J.; Wunsch, B. Conversion of a pentane-1,3,5-triol
̈
̈
NMDA, N-methyl-D-aspartate; PCP, phencyclidine (= 1-(1-
phenylcyclohexyl)piperidine); DIAD, diisopropyl azodicarbox-
ylate; PPh3, triphenylphosphane; SEM, standard error of the
mean; APCI, atmospheric-pressure chemical ionization; ATR,
attenuated total reflectance; fc, flash chromatography
derivative using lipases as chiral catalysts and possible function of the
lid for the regulation of substrate selectivity and enantioselectivity.
Biocatal. Biotransform. 2012, 30, 217−225.
(20) Harada, N.; Saito, A.; Ono, H.; Gawronski, J.; Gawronska, K.;
Sugioka, T.; Uda, H.; Kuriki, T. A CD method for determination of the
absolute stereochemistry of acyclic glycols. 1. Application of the CD
exciton chirality method to acyclic 1,3-dibenzoate systems. J. Am.
Chem. Soc. 1991, 113, 3842−3850.
(21) Bailey, W. F.; Connon, H.; Eliel, E. L.; Wiberg, K. B.
Calorimetric determination of the conformational enthalpy and
entropy of 2-phenyl-1,3-dioxane. Effectively free rotation of an
equatorial 2-phenyl group. Conformational equilibria in 2,2-
disubstituted 1,3-dioxanes. J. Am. Chem. Soc. 1978, 100, 2202−2209.
(22) Nader, F. W.; Eliel, E. L. Conformational analysis. XXII.
Conformational equilibria in 2-substituted 1,3-dioxanes. J. Am. Chem.
Soc. 1970, 92, 3050−3055.
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