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

Abstract

The C/Si/Ge-analogous compounds rac-Ph( c-C 5H 9)El(CH 2OH)CH 2CH 2NR 2 (NR 2=piperidino; El=C, rac- 3a; El=Si, rac- 3b; El=Ge, rac- 3c) and ( c-C 5H 9) 2El(CH 2OH)CH 2CH 2NR 2 (NR 2=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 M 1, M 2, M 3, M 4, and M 5 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 Ph 2El(CH 2OH)CH 2CH 2NR 2 (NR 2=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 M 1–M 5 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 M 1–M 5 receptors than their corresponding ( S)-antipodes (distomers), the stereoselectivity ratios being higher at M 1, M 3, M 4, and M 5 than at M 2 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 M 1–M 5 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 M 1–M 5 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 M 1/M 2 receptors (12.9-fold).