Structure-activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens

被引:185
作者
Ross, RA [1 ]
Gibson, TM
Brockie, HC
Leslie, M
Pashmi, G
Craib, SJ
Di Marzo, V
Pertwee, RG
机构
[1] Univ Aberdeen, Dept Biomed Sci, Inst Med Sci, Aberdeen AB25 2ZD, Scotland
[2] CNR, Ist Chim Mol Interesse Biol, Endocannabinoid Res Grp, I-80072 Arco Felice Napoli, Italy
关键词
anandamide; vanilloid; cannabinoid; VR1 transfected cells; structure-activity; mouse vas deferens; AM404; arvanil; capsaicin; RTX;
D O I
10.1038/sj.bjp.0703850
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 This study was directed at exploring the structure-activity relationship for anandamide and certain of its analogues at the rat VR1 receptor in transfected cells and at investigating the relative extent to which anandamide interacts with CB1 and vanilloid receptors in the mouse vas deferens. 2 pK(i) values for displacement of [H-3]-resiniferatoxin from membranes of rVR1 transfected CHO cells were significantly less for anandamide (5.78) than for its structural analogues N-(4 hydroxyphenyl)-arachidonylamide (AM404; 6.18) and N-(3 -methoxy-4-hydroxy)benzyl-arachidonylamide (arvanil; 6.77). 3 pEC(50) values for stimulating Ca-45(2+) uptake into rVR1 transfected CHO cells were significantly less for anandamide (5.80) than for AM404 (6.32) or arvanil (9.29). Arvanil was also significantly more potent than capsaicin (pEC(50) = 7.37), a compound with the same substituted benzyl polar head group as arvanil. 4 In the mouse vas deferens, resiniferatoxin was 218 times more potent than capsaicin as an inhibitor of electrically-evoked contractions. Both drugs were antagonized to a similar extent by capsazepine (pK(B)=6.93 and 7.18 respectively) but were not antagonized by SR141716A (1 muM). Anandamide was less susceptible than capsaicin to antagonism by capsazepine (pK(B) = 6.02) and less susceptible to antagonism by SR141716A (pK(B)=8.66) than methanandamide (pK(B)=9.56). WIN55212 was antagonized by SR141716A (pK(B)=9.02) but not by capsazepine (10 muM). 5 In conclusion, anandamide and certain of its analogues have affinity and efficacy at the rat VR1 receptor. In the mouse vas deferens, which seems to express vanilloid and CB1 receptors, both receptor types appear to contribute to anandamide-induced inhibition of evoked contractions.
引用
收藏
页码:631 / 640
页数:10
相关论文
共 27 条
[1]   CAPSAZEPINE - A COMPETITIVE ANTAGONIST OF THE SENSORY NEURON EXCITANT CAPSAICIN [J].
BEVAN, S ;
HOTHI, S ;
HUGHES, G ;
JAMES, IF ;
RANG, HP ;
SHAH, K ;
WALPOLE, CSJ ;
YEATS, JC .
BRITISH JOURNAL OF PHARMACOLOGY, 1992, 107 (02) :544-552
[2]  
CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099
[3]  
Colquhoun D., 1971, LECT BIOSTATISTICS
[4]   Evidence that methyl arachidonyl fluorophosphate is an irreversible cannabinoid receptor antagonist [J].
Fernando, SR ;
Pertwee, RG .
BRITISH JOURNAL OF PHARMACOLOGY, 1997, 121 (08) :1716-1720
[5]   Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances [J].
Hwang, SW ;
Cho, H ;
Kwak, J ;
Lee, SY ;
Kang, CJ ;
Jung, J ;
Cho, S ;
Min, KH ;
Suh, YG ;
Kim, D ;
Oh, U .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (11) :6155-6160
[6]  
Jerman J. C., 2000, British Journal of Pharmacology, V129, p73P
[7]  
Jung J, 1999, J NEUROSCI, V19, P529
[8]  
KENAKIN T, 1997, PHARM ANAL DRUG RECE, P271
[9]   Substrate specificity and stereoselectivity of rat brain microsomal anandamide amidohydrolase [J].
Lang, WS ;
Qin, C ;
Lin, SY ;
Khanolkar, AD ;
Goutopoulos, A ;
Fan, PS ;
Abouzid, K ;
Meng, ZX ;
Biegel, D ;
Makriyannis, A .
JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (05) :896-902
[10]   A COMPARISON OF CAPSAZEPINE AND RUTHENIUM RED AS CAPSAICIN ANTAGONISTS IN THE RAT ISOLATED URINARY-BLADDER AND VAS-DEFERENS [J].
MAGGI, CA ;
BEVAN, S ;
WALPOLE, CSJ ;
RANG, HP ;
GIULIANI, S .
BRITISH JOURNAL OF PHARMACOLOGY, 1993, 108 (03) :801-805