182305-41-5Relevant articles and documents
Pharmacological discrimination between enantiomeric germanes by muscarinic receptors: A study on germanium/silicon bioisosterism
Tacke, Reinhold,Reichel, Dirk,Jones, Peter G.,Hou, Xue,Waelbroeck, Magali,Gross, Jan,Mutschler, Ernst,Lambrecht, Guenter
, p. 305 - 323 (2007/10/03)
The (hydroxymethyl)diorgano(2-piperidinoethyl)germanes rac-Ph(c-Hex)Ge(CH2OH)CH2CH2NR2 (rac-1a), Ph2Ge(CH2OH)CH2CH2NR2 (3a) and (c-Hex)2Ge(CH2OH)CH2CH2NR2 (5a) (NR2 = piperidino) were synthesized starting from Cl3GeCH2Cl. The (R)-and (S)-enantiomer of 1a were obtained by resolution of rac-1a using the antipodes of O,O′-di-p-toluoyltartaric acid as resolving agents (resolution by fractional crystallization of diastereomeric salts). The enantiomeric purities of the resolved antipodes of 1a were shown to be at least 98 (1H NMR) and 97% ee (13C NMR) respectively (NMR studies using a chiral shift reagent). Reaction of rac-1a, (R)-1a, (S)-1a, 3a and 5a with methyl iodide gave the corresponding methiodides rac-2a, (R)-2a, (S)-2a, 4a and 6a (1a → 2a, 3a → 4a, 5a → 6a). The absolute configuration of (R)-2a was determined by single-crystal X-ray diffraction. On the basis of the experimentally established absolute configuration of (R)-2a, the absolute configurations of all the other aforementioned optically active germanium compounds were assigned by chemical and optical correlations. The enantiomerically pure germanium compounds (R)-1a, (S)-1a, (R)-2a and (S)-2a and their achiral derivatives 3a-6a were studied for their affinities for muscarinic M1, M2, M3 and M4 receptors by functional pharmacological experiments (M1, rabbit vas deferens; M2, guinea-pig atria; M3, guinea-pig ileum) and radioligand binding experiments (M1, human NB-OK 1 cells; M2, rat heart; M3, rat pancreas; M4, rat striatum). The receptor affinities obtained in these studies were compared with those of the related silicon analogues, the (hydroxymethyl)diorgano(2-piperidinoethyl)silanes (R)-and (S)-Ph(c-Hex)Si(CH2OH)CH2CH2NR2 [(R)-1b and (S)-1b], Ph2Si(CH2OH)CH2CH2NR2 (3b) and (c-Hex)2Si(CH2OH)CH2CH2NR2 (5b) (NR2 = piperidino) and their corresponding methiodides (R)-2b, (S)-2b, 4b and 6b (a → b: Ge → Si; studies on Ge/Si bioisosterism). According to these studies, all the germanes and the related silicon analogues behaved as simple competitive antagonists at muscarinic M1-M4 receptors. The pKi values obtained in binding studies at M1-M3 receptors were similar to the corresponding functional affinities (pA2 values). The receptor affinities of the respective Ge/Si analogues were found to be very similar, indicating a strongly pronounced Ge/Si bioisosterism. The (R)-enantiomers (eutomers) of the Ge/Si pairs 1a/1b and 2a/2b exhibited higher affinities (up to 26-fold) for M1-M4 receptors than their corresponding (S)-antipodes (distomers), the stereoselectivity ratios being higher at M1, M3 and M4 than at M2 receptors. In most cases, the diphenyl (3a/3b and 4a/4b) and dicyclohexyl (5a/5b and 6a/6b) compounds displayed lower affinities to M1-M4 receptors than the related (R)-enantiomers of 1a/1b and 2a/2b, and the sums of the respective affinity differences were very similar to the experimentally established stereoselectivity ratios [(R)/(S)]. Thus, the stereoselective interaction of the enantiomers of 1a/1b and 2a/2b with muscarinic receptors is best explained in terms of opposite and weaker binding of the phenyl and cyclohexyl ring of the (S)-antipodes. The highest receptor selectivity was observed for compound (R)-1b at M1/M2 receptors (25-fold in binding studies).
