Axial chirality and affinity at the GABAA receptor of pyrimido[1,2-a][1,4]benzodiazepines and related compounds

Shoukou Lee; Tomonori Kamide; Hidetsugu Tabata; Hideyo Takahashi; Motoo Shiro; Hideaki Natsugari

doi:10.1016/j.bmc.2008.09.037

Axial chirality and affinity at the GABA_A receptor of pyrimido[1,2-a][1,4]benzodiazepines and related compounds

Shoukou Lee
, Tomonori Kamide
, Hidetsugu Tabata
, Hideyo Takahashi
, Motoo Shiro
, Hideaki Natsugari

Faculty of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

Abstract

The pyrimido[1,2-a][1,4]benzodiazepines (1a-c) and the 8-membered analogues (diazocines 2a and 2b) were separated into their atropisomers with HPLC on a chiral column. High stereochemical stability was observed in the atropisomer of the 8-membered derivatives (2a and 2b), and the 1,4-benzodiazepine (1c) with 2′-chloro at the pendant phenyl showed a lower energy barrier for the conversion between the atropisomers compared with that with the unsubstituted pendant phenyl (1a). The aR isomer of 1a-c was revealed to be the eutomer in GABA_A receptor binding, and the eutomer 1c-R showed extremely potent activity with an IC₅₀ value of 1.5 nM.

Original language	English
Pages (from-to)	9519-9523
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry
Volume	16
Issue number	21
DOIs	https://doi.org/10.1016/j.bmc.2008.09.037
State	Published - 1 Nov 2008

Keywords

Atropisomer
Estazolam
GABA receptor
Pyrimido[1,2- a][1,4]benzodiazepine
Triazolam
X-ray analysis

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10.1016/j.bmc.2008.09.037

Cite this

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title = "Axial chirality and affinity at the GABAA receptor of pyrimido[1,2-a][1,4]benzodiazepines and related compounds",

abstract = "The pyrimido[1,2-a][1,4]benzodiazepines (1a-c) and the 8-membered analogues (diazocines 2a and 2b) were separated into their atropisomers with HPLC on a chiral column. High stereochemical stability was observed in the atropisomer of the 8-membered derivatives (2a and 2b), and the 1,4-benzodiazepine (1c) with 2′-chloro at the pendant phenyl showed a lower energy barrier for the conversion between the atropisomers compared with that with the unsubstituted pendant phenyl (1a). The aR isomer of 1a-c was revealed to be the eutomer in GABAA receptor binding, and the eutomer 1c-R showed extremely potent activity with an IC50 value of 1.5 nM.",

keywords = "Atropisomer, Estazolam, GABA receptor, Pyrimido[1,2- a][1,4]benzodiazepine, Triazolam, X-ray analysis",

author = "Shoukou Lee and Tomonori Kamide and Hidetsugu Tabata and Hideyo Takahashi and Motoo Shiro and Hideaki Natsugari",

year = "2008",

month = nov,

day = "1",

doi = "10.1016/j.bmc.2008.09.037",

language = "英語",

volume = "16",

pages = "9519--9523",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Ltd",

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T1 - Axial chirality and affinity at the GABAA receptor of pyrimido[1,2-a][1,4]benzodiazepines and related compounds

AU - Lee, Shoukou

AU - Kamide, Tomonori

AU - Tabata, Hidetsugu

AU - Takahashi, Hideyo

AU - Shiro, Motoo

AU - Natsugari, Hideaki

PY - 2008/11/1

Y1 - 2008/11/1

N2 - The pyrimido[1,2-a][1,4]benzodiazepines (1a-c) and the 8-membered analogues (diazocines 2a and 2b) were separated into their atropisomers with HPLC on a chiral column. High stereochemical stability was observed in the atropisomer of the 8-membered derivatives (2a and 2b), and the 1,4-benzodiazepine (1c) with 2′-chloro at the pendant phenyl showed a lower energy barrier for the conversion between the atropisomers compared with that with the unsubstituted pendant phenyl (1a). The aR isomer of 1a-c was revealed to be the eutomer in GABAA receptor binding, and the eutomer 1c-R showed extremely potent activity with an IC50 value of 1.5 nM.

AB - The pyrimido[1,2-a][1,4]benzodiazepines (1a-c) and the 8-membered analogues (diazocines 2a and 2b) were separated into their atropisomers with HPLC on a chiral column. High stereochemical stability was observed in the atropisomer of the 8-membered derivatives (2a and 2b), and the 1,4-benzodiazepine (1c) with 2′-chloro at the pendant phenyl showed a lower energy barrier for the conversion between the atropisomers compared with that with the unsubstituted pendant phenyl (1a). The aR isomer of 1a-c was revealed to be the eutomer in GABAA receptor binding, and the eutomer 1c-R showed extremely potent activity with an IC50 value of 1.5 nM.

KW - Atropisomer

KW - Estazolam

KW - GABA receptor

KW - Pyrimido[1,2- a][1,4]benzodiazepine

KW - Triazolam

KW - X-ray analysis

UR - https://www.scopus.com/pages/publications/53749105016

U2 - 10.1016/j.bmc.2008.09.037

DO - 10.1016/j.bmc.2008.09.037

M3 - 記事

C2 - 18829330

AN - SCOPUS:53749105016

SN - 0968-0896

VL - 16

SP - 9519

EP - 9523

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 21

ER -

Axial chirality and affinity at the GABA_A receptor of pyrimido[1,2-a][1,4]benzodiazepines and related compounds

Abstract

Keywords

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CCDC 701683: Experimental Crystal Structure Determination

CCDC 701682: Experimental Crystal Structure Determination

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Axial chirality and affinity at the GABAA receptor of pyrimido[1,2-a][1,4]benzodiazepines and related compounds

Abstract

Keywords

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Datasets

CCDC 701683: Experimental Crystal Structure Determination

CCDC 701682: Experimental Crystal Structure Determination

Cite this

Axial chirality and affinity at the GABA_A receptor of pyrimido[1,2-a][1,4]benzodiazepines and related compounds