Design, synthesis and biological activity of rigid cannabinoid CB1 receptor antagonists

被引：59

作者：

Stoit, AR ^{[1
]}

Lange, JHM ^{[1
]}

den Hartog, AP ^{[1
]}

Ronken, E ^{[1
]}

Tipker, K ^{[1
]}

van Stuivenberg, HH ^{[1
]}

Dijksman, JAR ^{[1
]}

Wals, HC ^{[1
]}

Kruse, CG ^{[1
]}

机构：

[1] Solvay Pharmaceut Res Labs, NL-1380 DA Weesp, Netherlands

来源：

CHEMICAL & PHARMACEUTICAL BULLETIN | 2002年 / 50卷 / 08期

关键词：

benzocycloheptapyrazole; CB1 receptor antagonist; molecular modeling; regiochemistry;

D O I：

10.1248/cpb.50.1109

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated alpha,gamma-keto ester adduct (4). The optimal nitroderivative (28) in this series exhibits a high CB1 receptor affinity (pK(i)=7.2) as well as very potent antagonistic activity (pA(2)=8.8) in vitro. The regioselectivity of the pyrazole ring closure is shown to depend strongly on the aromatic substitution pattern of the applied arylhydrazine.

引用

页码：1109 / 1113

页数：5

共 50 条

[41] Allosteric Modulation of Cannabinoid CB1 Receptor
Ross, Ruth A.
Baillie, Gemma L.
Pertwee, Roger G.
FASEB JOURNAL, 2012, 26
[42] Internalization and recycling of the CB1 cannabinoid receptor
Hsieh, C
Brown, S
Derleth, C
Mackie, K
JOURNAL OF NEUROCHEMISTRY, 1999, 73 (02) : 493 - 501
[43] Allosteric modulation of the cannabinoid CB1 receptor
Price, MR
Baillie, GL
Thomas, A
Stevenson, LA
Easson, M
Goodwin, R
McLean, A
McIntosh, L
Goodwin, G
Walker, G
Westwood, P
Marrs, J
Thomson, F
Cowley, P
Christopoulos, A
Pertwee, RG
Ross, RA
MOLECULAR PHARMACOLOGY, 2005, 68 (05) : 1484 - 1495
[44] Effects of castration on cannabinoid CB1 receptor expression and on the biological actions of cannabinoid in the parotid gland
Busch, L
Sterin-Borda, L
Borda, E
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 2006, 33 (03): : 258 - 263
[45] Signal transduction of the CB1 cannabinoid receptor
Turu, Gabor
Hunyady, Laszlo
JOURNAL OF MOLECULAR ENDOCRINOLOGY, 2010, 44 (02) : 75 - 85
[46] Biphasic suppression of appetite by cannabinoid CB1 receptor antagonists with distinct functional activities
Lin, Yinchiu
Shia, Kak-Shan
Hsiao, Wen-Chi
Hsieh, Wan-Ping
Yeh, Teng-Kuang
Tseng, Shi-Liang
Hsu, Chia-Yu
Chao, Yu-Sheng
Hung, Ming-Shiu
PHARMACOLOGICAL RESEARCH, 2010, 62 (04) : 337 - 343
[47] The discovery of novel indole-2-carboxamides as cannabinoid CB1 receptor antagonists
Cowley, Phillip M.
Baker, James
Barn, David R.
Buchanan, Kirsteen I.
Carlyle, Ian
Clark, John K.
Clarkson, Thomas R.
Deehan, Maureen
Edwards, Darren
Goodwin, Richard R.
Jaap, David
Kiyoi, Yasuko
Mort, Chris
Palin, Ronald
Prosser, Alan
Walker, Glenn
Ward, Nick
Wishart, Grant
Young, Trevor
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (01) : 497 - 501
[48] Discovery of indole alkaloids with cannabinoid CB1 receptor antagonistic activity
Kitajima, Mariko
Iwai, Masumi
Kikura-Hanajiri, Ruri
Goda, Yukihiro
Iida, Mitsuru
Yabushita, Hisatoshi
Takayama, Hiromitsu
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (07) : 1962 - 1964
[49] CB1 cannabinoid receptor antagonists for treatment of obesity and prevention of comorbid metabolic disorders
Antel, Jochen
Gregory, Peter C.
Nordheim, Ulrich
JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (14) : 4008 - 4016
[50] Expression and biological effects of CB1 cannabinoid receptor in rat parotid gland
Busch, L
Sterin-Borda, L
Borda, E
BIOCHEMICAL PHARMACOLOGY, 2004, 68 (09) : 1767 - 1774

← 1 2 3 4 5 →