405072-08-4Relevant academic research and scientific papers
Syntheses and pharmacological characterization of achiral and chiral enantiopure C/Si/Ge-analogous derivatives of the muscarinic antagonist cycrimine: A study on C/Si/Ge bioisosterism
Tacke, Reinhold,Kornek, Thomas,Heinrich, Tilman,Burschka, Christian,Penka, Martin,Pülm, Melanie,Keim, Christine,Mutschler, Ernst,Lambrecht, Günter
, p. 140 - 165 (2007/10/03)
The C/Si/Ge-analogous compounds rac-Ph(c-C5H9)El(CH2OH)CH2CH 2NR2 (NR2=piperidino; El=C, rac-3a; El=Si, rac-3b; El=Ge, rac-3c) and (c-C5H9)2El(CH2OH)CH 2CH2NR2 (NR2=piperidino; El=C, 5a; El=Si, 5b; El=Ge, 5c) were prepared in multi-step syntheses. The (R)- and (S)-enantiomers of 3a-c were obtained by resolution of the respective racemates using the antipodes of O,O′-dibenzoyltartaric acid (resolution of rac-3a), O,O′-di-p-toluoyltartaric acid (resolution of rac-3b), or 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (resolution of rac-3c). The enantiomeric purities of (R)-3a-c and (S)-3a-c were ≥98% ee (determined by 1H-NMR spectroscopy using a chiral solvating agent). Reaction of rac-3a-c, (R)-3a-c, (S)-3a-c, and 5a-c with methyl iodide gave the corresponding methylammonium iodides rac-4a-c, (R)-4a-c, (S)-4a-c, and 6a-c (3a-c→4a-c; 5a-c→6a-c). The absolute configuration of (S)-3a was determined by a single-crystal X-ray diffraction analysis of its (R,R)-O,O′-dibenzoyltartrate. The absolute configurations of the silicon analog (R)-4b and germanium analog (R)-4c were also determined by single-crystal X-ray diffraction. The chiroptical properties of the (R)- and (S)-enantiomers of 3a-c, 3a-c·HCl, and 4a-c were studied by ORD measurements. In addition, the C/Si/Ge analogs (R)-3a-c, (S)-3a-c, (R)-4a-c, (S)-4a-c, 5a-c, and 6a-c were studied for their affinities at recombinant human muscarinic M1, M2, M3, M4, and M5 receptors stably expressed in CHO-K1 cells (radioligand binding experiments with [3H]N-methylscopolamine as the radioligand). For reasons of comparison, the known C/Si/Ge analogs Ph2El(CH2OH)CH2CH2NR2 (NR2=piperidino; El=C, 7a; El=Si, 7b; El=Ge, 7c) and the corresponding methylammonium iodides 8a-c were included in these studies. According to these experiments, all the C/Si/Ge analogs behaved as simple competitive antagonists at M1-M5 receptors. The receptor subtype affinities of the individual carbon, silicon, and germanium analogs 3a-8a, 3b-8b, and 3c-8c were similar, indicating a strongly pronounced C/Si/Ge bioisosterism. The (R)-enantiomers (eutomers) of 3a-c and 4a-c exhibited higher affinities (up to 22.4 fold) for M1-M5 receptors than their corresponding (S)-antipodes (distomers), the stereoselectivity ratios being higher at M1, M3, M4, and M5 than at M2 receptors, and higher for the methylammonium compounds (4a-c) than for the amines (3a-c). With a few exceptions, compounds 5a-c, 6a-c, 7a-c, and 8a-c displayed lower affinities for M1-M5 receptors than the related (R)-enantiomers of 3a-c and 4a-c. The stereoselective interaction of the enantiomers of 3a-c and 4a-c with M1-M5 receptors is best explained in terms of opposite binding of the phenyl and cyclopentyl ring of the (R)- and (S)-enantiomers. The highest receptor subtype selectivity was observed for the germanium compound (R)-4c at M1/M2 receptors (12.9-fold).
