Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy.: 1.: Mapping the central 5-HT3 receptor binding site by arylpiperazine derivatives

被引:83
作者
Cappelli, A
Anzini, M
Vomero, S
Mennuni, L
Makovec, F
Doucet, E
Hamon, M
Bruni, G
Romeo, MR
Menziani, MC
De Benedetti, PG
Langer, T
机构
[1] Univ Siena, Dipartimento Farmacochim Tecnol, I-53100 Siena, Italy
[2] Rotta Res Lab SpA, I-20052 Monza, Italy
[3] Univ Paris 06, INSERM, U288, F-75634 Paris 13, France
[4] Univ Siena, Ist Farmacol, I-53100 Siena, Italy
[5] Univ Modena, Dipartimento Chim, I-41100 Modena, Italy
[6] Univ Innsbruck, Inst Pharmaceut Chem, A-6020 Innsbruck, Austria
关键词
D O I
10.1021/jm970645i
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Synthesis and pharmacological evaluation of a series of condensed quinoline and pyridine derivatives bearing a N-methylpiperazine moiety attached to the 2-position of the quinoline or pyridine nucleus are described. 5-HT receptor binding studies revealed subnanomolar affinity for the 5-HT3 receptor subtype in some of the compounds under study. The most active compound (5b) displayed a K-i value about 1 order of magnitude higher than that of quipazine along with a higher selectivity. The potential 5-HT3 agonist/antagonist activity of four selected compounds was assessed in vitro on 5-HT3 receptor-dependent [C-14]guanidinium uptake in NG 108-15 cells. Compound 5j acted as a 5-HT3 agonist in this assay with an EC50 value close to that reported for quipazine, while 5b was a partial agonist with an EC50 value of about 0.25 nM, and compound 5c possessed antagonist properties with an IC50 value (approximate to 8 nM) in the same range as those of previously characterized 5-HT3 receptor antagonists. Qualitative and quantitative structure-affinity relationship studies carried out by making use of theoretical molecular descriptors allowed to elucidate the role of the main pharmacophoric components and to develop a model for the interaction of the 5-HT3 ligands related to quipazine with their receptor.
引用
收藏
页码:728 / 741
页数:14
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