Sila-analogues of high-affinity, selective σ ligands of the spiro[indane-1,4′-piperidine] type:: Syntheses, structures, and pharmacological properties

被引:59
作者
Tacke, R [1 ]
Handmann, VI
Bertermann, R
Burschka, C
Penka, M
Seyfried, C
机构
[1] Univ Wurzburg, Inst Inorgan Chem, D-97074 Wurzburg, Germany
[2] Merck KGaA, Dept CNS Res Biomed Res, D-64293 Darmstadt, Germany
关键词
D O I
10.1021/om020354u
中图分类号
O61 [无机化学];
学科分类号
070301 ; 081704 ;
摘要
The 1'-organylspiro[indane-1,4'-piperidine] derivatives 1a-4a (organyl = benzyl (la), 4-methoxybenzyl (2a), 2-phenylethyl (3a), 3-methylbut-2-enyl (4a)) are high-affinity, selective sigma ligands. The corresponding sila-analogues 1b-4b (--> replacement of the carbon spirocenter by a silicon atom) were synthesized in three-step syntheses, starting from dichlorodivinylsilane, and were isolated as the hydrochlorides 1b . HCl-4b . HCl. To get information about the structure of the title compounds and their respective carbon analogues in the solid state and in solution, crystal structure analyses (1a . HCl, 2a, 2b-HCl) and temperature-dependent solution H-1 NMR studies (2a . HCl, 2b-HCl) were performed. These structural investigations were complemented by computational studies of related model species. The C/Si pairs 1a/1b-4a/4b were studied for their affinities for various central nervous system receptors (sigma, 5-HT1A, 5-HT2A, alpha(1), alpha(2), M, D-2) using radioligand binding assays. The sigma affinities of the sila-analogues 2b-4b were found to be similar to those of the parent carbon compounds 2a-4a, whereas sila-substitution of 1a (--> 1b) resulted in a decrease of affinity of about 1 order of magnitude. On the other hand, a significant increase of affinity for the dopamine D-2 and the serotonin 2A (5-HT2A) receptors was observed for the sila-analogues 1b-4b, the sila-substitution effect being especially pronounced for 4a/4b (6-fold affinity increase for the D-2 receptor) and 3a/3b (37-fold affinity increase for the 5-HT2A receptor).
引用
收藏
页码:916 / 924
页数:9
相关论文
共 27 条
[1]   ELECTRONIC-STRUCTURE CALCULATIONS ON WORKSTATION COMPUTERS - THE PROGRAM SYSTEM TURBOMOLE [J].
AHLRICHS, R ;
BAR, M ;
HASER, M ;
HORN, H ;
KOLMEL, C .
CHEMICAL PHYSICS LETTERS, 1989, 162 (03) :165-169
[2]  
[Anonymous], 2015, Acta Crystallogr., V71, P3
[3]  
Bowen W D, 2000, Pharm Acta Helv, V74, P211
[4]  
BRAUN S, 1996, 100 MORE BASIC NMR E, P115
[5]   SPIROPIPERIDINES AS HIGH-AFFINITY, SELECTIVE SIGMA-LIGANDS [J].
CHAMBERS, MS ;
BAKER, R ;
BILLINGTON, DC ;
KNIGHT, AK ;
MIDDLEMISS, DN ;
WONG, EHF .
JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (11) :2033-2039
[6]   THE SELECTIVE LABELING OF CENTRAL 5-HT1A RECEPTOR-BINDING SITES BY [H-3] 5-METHOXY-3-(DI-NORMAL-PROPYLAMINO)CHROMAN [J].
COSSERY, JM ;
GOZLAN, H ;
SPAMPINATO, U ;
PERDICAKIS, C ;
GUILLAUMET, G ;
PICHAT, L ;
HAMON, M .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1987, 140 (02) :143-155
[7]   Towards 2-silaallenes: Synthesis of spirocyclic precursors [J].
Goetze, B ;
Herrschaft, B ;
Auner, N .
CHEMISTRY-A EUROPEAN JOURNAL, 1997, 3 (06) :948-957
[8]   Five- and six-membered silicon-carbon heterocycles. Part 1. Synthetic methods for the construction of silacycles [J].
Hermanns, J ;
Schmidt, B .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1998, (14) :2209-2230
[9]   Five- and six-membered silicon-carbon heterocycles. Part 2. Synthetic modifications and applications of silacycles [J].
Hermanns, J ;
Schmidt, B .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1999, (02) :81-102
[10]  
KLOCKOW M, 1986, ARZNEIMITTEL-FORSCH, V36-1, P197