Synthesis and pharmacological properties of silicon-containing 1,4-dihydropyridine derivatives:: calcium channel antagonists and α1 adrenoceptor antagonists of the sila-niguldipine type

被引:23
作者
Heinrich, T
Burschka, C
Warneck, J
Tacke, R [1 ]
机构
[1] Univ Wurzburg, Inst Anorgan Chem, D-97074 Wurzburg, Germany
[2] Amedis Pharmaceut Ltd, Cambridge CB4 0GP, England
关键词
D O I
10.1021/om0305622
中图分类号
O61 [无机化学];
学科分类号
070301 ; 081704 ;
摘要
Racemic 3-(4,4-diphenyl-4-silapiperidin-1-yl)propyl methyl 2,6-dimethyl-4-(3-nitrophenyl)1,4-dihydropyridine-3,5-dicarboxylate (rac-sila-niguldipine, rac-1b), a sila analogue of the calcium antagonist rac-niguldipine (rac-1a), and the sila-niguldipine derivatives rac-2b-rac-4b were synthesized in multistep syntheses, starting from dichlorodiphenylsilane. The silicon compounds rac-1b-rac-4b contain a 4,4-diphenyl-4-silapiperidin-1-yl group instead of the 4,4-diphenylpiperidin-1-yl moiety in the parent carbon compound rac-1a. rac-Silaniguldipine and the precursor 3-(4,4-diphenyl-4-silapiperidin-1-yl)propanol (11) were structurally characterized by single-crystal X-ray diffraction. The pharmacological profiles of rac-1b-rac-4b were compared with that of rac-la across a range of receptor binding assays (radioligand binding studies at alpha(1A) and alpha(2) adrenoceptors, the L-type Ca2+ channel, and the serotonin 5-HT receptor). The silicon compounds rac-2b-rac-4b exhibit a profile similar to that of SNAP 5089 and therefore may be of potential benefit in the treatment of diseases such as benign prostatic hyperplasia (BPH).
引用
收藏
页码:361 / 366
页数:6
相关论文
共 36 条
[1]  
[Anonymous], 2015, Acta Crystallogr., V71, P3
[2]  
Bains W, 2003, CURR OPIN DRUG DISC, V6, P526
[3]   (+)-NIGULDIPINE BINDS WITH VERY HIGH-AFFINITY TO CA-2+ CHANNELS AND TO A SUBTYPE OF ALPHA-1-ADRENOCEPTORS [J].
BOER, R ;
GRASSEGGER, A ;
SCHUDT, C ;
GLOSSMANN, H .
EUROPEAN JOURNAL OF PHARMACOLOGY-MOLECULAR PHARMACOLOGY SECTION, 1989, 172 (02) :131-145
[4]  
BOYAJIAN CL, 1987, J PHARMACOL EXP THER, V241, P1092
[5]   HETEROGENEOUS H-3 RAUWOLSCINE BINDING-SITES IN RAT CORTEX - 2 ALPHA-2-ADRENOCEPTOR SUBTYPES OR AN ADDITIONAL NON-ADRENERGIC INTERACTION [J].
BROADHURST, AM ;
ALEXANDER, BS ;
WOOD, MD .
LIFE SCIENCES, 1988, 43 (01) :83-92
[6]  
CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099
[7]  
Conti C R, 1996, Am J Cardiol, V78, P13, DOI 10.1016/S0002-9149(96)00733-3
[8]   N+/Si replacement as a tool for probing the pharmacophore of allosteric modulators of muscarinic M2 receptors:: Synthesis, allosteric potency, and positive cooperativity of silicon-based W84 derivatives [J].
Daiss, JO ;
Duda-Johner, S ;
Burschka, C ;
Holzgrabe, U ;
Mohr, K ;
Tacke, R .
ORGANOMETALLICS, 2002, 21 (05) :803-811
[9]   Synthesis and pharmacological characterization of new silicon-based W84-type allosteric modulators for ligand binding to muscarinic M2 receptors [J].
Duda-Johner, S ;
Daiss, JO ;
Mohr, K ;
Tacke, R .
JOURNAL OF ORGANOMETALLIC CHEMISTRY, 2003, 686 (1-2) :75-83
[10]   THE BINDING OF [H-3]-LABELED NITRENDIPINE TO RECEPTORS FOR CALCIUM-CHANNEL ANTAGONISTS IN THE HEART, CEREBRAL-CORTEX, AND ILEUM OF RATS [J].
EHLERT, FJ ;
ROESKE, WR ;
ITOGA, E ;
YAMAMURA, HI .
LIFE SCIENCES, 1982, 30 (25) :2191-2202