Fluorine-containing derivatives of the muscarinic antagonists sila-pridinol and sila-difenidol: Syntheses and antimuscarinic properties

• Published in: Journal of organometallic chemistry Vol. 501; no. 1; pp. 145 - 154
• Main Authors: Tacke, Reinhold, Terunuma, Daiyo, Tafel, Andrea, Mühleisen, Mathias, Forth, Bernhard, Waelbroeck, Magali, Gross, Jan, Mutschler, Ernst, Friebe, Thomas, Lambrecht, Günter
• Format: Journal Article
• Language: English
• Published: LAUSANNE 1 Elsevier B.V 04.10.1995; Elsevier
• Subjects: Chemistry; Chemistry, Inorganic & Nuclear; Chemistry, Organic; Muscarinic receptor subtypes; Physical Sciences; Science & Technology; Si/C bioisosterism; Sila-difenidol; Sila-pridinol; Sila-pridinol; Si/C bioisosterism; Sila-difenidol; Muscarinic receptor subtypes; SI/C BIOISOSTERISM; MUSCARINIC RECEPTOR SUBTYPES; SILA-PRIDINOL; SILA-DIFENIDOL
• ISSN: 0022-328X; 1872-8561
• DOI: 10.1016/0022-328X(95)05622-V

The fluorine-containing sila-pridinol and sila-difenidol derivatives p-fluoro-sila-pridinol ( 5a), p,p′-difluoro-sila-pridinol ( 6a), p-fluoro-sila-difenidol ( 7a), p,p′-difluoro-sila-difenidol ( 8a), p-fluoro-sila-difenidol methiodide ( 9a) and p,p′-difluoro-sila-difenidol methiodide ( l0a) were synthesized, starting from the silanes Cl 3SiCHCH 2 ( 5a and 6a) and (CH 3O) 3Si(CH 2) 3Cl ( 7a–10a) respectively. The chiral compounds 5a, 7a and 9a were obtained as racemic mixtures. The muscarinic pharmacology of the silanols 5a–10a was studied and compared with that of their carbon analogues, the carbinols 5b–10b (studies on silicon-carbon bioisosterism). The affinities and receptor selectivities (Ml–M4 receptors) of the SiC pairs 5a/5b–l0a/l0b were found to depend on the following structural parameters: length of the carbon chain El-(CH 2) n -N (El  Si or C; n = 2, 3), N-methylation, fluorine substitution of the phenyl rings and the nature of the central atom (silicon or carbon). Most interestingly, replacement of the central carbinol carbon atom in p-fluoro-difenidol methiodide ( 9b) by a silicon atom (→ 9a) leads to an increase in affinity for muscarinic receptor subtypes by factors of 32–81. Such a high increase in biological activity by sila-substitution (CSi exchange) has not yet been reported.