IN-VIVO PROPERTIES OF SB 200646A, A 5-HT2C/2B RECEPTOR ANTAGONIST

被引:174
作者
KENNETT, GA [1 ]
WOOD, MD [1 ]
GLEN, A [1 ]
GREWAL, S [1 ]
FORBES, I [1 ]
GADRE, A [1 ]
BLACKBURN, TP [1 ]
机构
[1] SMITHKLINE BEECHAM,DEPT MED CHEM,HARLOW CM19 5AD,ESSEX,ENGLAND
关键词
5-HT2C RECEPTORS; 5-HT2A RECEPTORS; 5-HT2B RECEPTORS; 5-HT; ANXIETY; SB; 200646A;
D O I
10.1111/j.1476-5381.1994.tb14808.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 SB 200646A, N-(1-methyl-5-indolyl)-N-(3-pyridyl) urea hydro chloride, the first reported selective 5-HT2C/2B over 5-HT2A receptor antagonist, (pK(l) rat 5-HT2C receptor 6.9, pA(2) rat 5-HT2B receptor 7.5, pK(l) rat 5-HT2A receptor 5.2) dose-dependently blocked a putative rat model of 5-HT2C receptor activation; 1-(3-chlorophenyl)piperazine (mCPP, 5 mg kg(-1), i.p. 20 min pretest)-induced hypolocomotion (estimated ID50 19.2 mg kg(-1), p.o.). 2 SB 200646A also blocked another putative in vivo model of 5-HT2C receptor function; mCPP (5 mg kg(-1), i.p. 20 min pretest)-induced hypophagia in 23 h food-deprived rats (estimated ID50 18.3 mg kg(-1), p.o.). 3 SB 200646A did not antagonize 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head shakes in rats at doses up to 200 mg kg(-1), p.o., an effect thought to be mediated by 5-HT2A receptors for which SB 200646A has its next highest affinity (50 fold less) after the 5-HT2C and 5-HT2B sites. 4 SB 200646A (20, 40 mg kg(-1), p.o., 1h pretest) also reversed mCPP (0.5 mg kg(-1), i.p., 30 min pretest)-induced anxiety in the social interaction test, under low light familiar conditions. 5 When given alone, under high light unfamiliar conditions, SB 200646A (2-40 mg kg(-1), p.o.) increased active social interaction without affecting locomotor activity in the rat social interaction test. This is consistent with an anxiolytic action of SB 200646A. 6 These results indicate that SB 200646A has in vivo efficacy and that 5-HT2C or 5-HT2B receptors are indeed likely to mediate mCPP-induced hypolocomotion, hypophagia and anxiogenesis. They also suggest that 5-HT2C/2B receptor blockade induces anxiolysis.
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页码:797 / 802
页数:6
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