Synthesis, antimuscarinic activity and quantitative structure-activity relationship (QSAR) of tropinyl and piperidinyl esters

Article abstract of DOI:10.1248/cpb.46.231

A series of tropinyl and piperidinyl esters was synthesized and evaluated for inhibitory activities on the endothelial muscarinic receptors of rat (M₃) and rabbit (M₂) aorta. Some of the esters (cyclohexylphenylglycolates and cyclohexylphenylpropionates) were found to be better antimuscarinic compounds than standard M₂ and M₃ inhibitors such as AFDX116 and 4-diphenylacetoxy-N-methylpiperidine (DAMP), with pKEC₅₀ values in the range of 8-9. A few esters were found to be more selective M₃ than M₂ inhibitors, but these tended to have low activities. The hydrophobic, electronic and steric characteristics of these esters were correlated with antimuscarinic activity by using appropriate parameters representing hydrophobicity (HPLC capacity factor, log k(w), size (molecular volume) and electronic character (Taft's polar substituent constant δ and ¹³C chemical shift difference Δδ). Finally, 92% of the M₂-inhibitory activities of the esters could be accounted for by the size and electronic character σ* of the side chain. In contrast, the M₃-inhibitory activities of these esters were mainly attributed to the electronic nature (σ*, Δδ) of the side chain, with good activity being associated with electron-withdrawing groups. Visualization of the comparative molecular field analysis (CoMFA) steric and electrostatic fields provided further confirmation of the structure-activity relationship (SAR) derived from traditional quantitative structure-activity relationship (QSAR) approaches.

Full text of DOI:10.1248/cpb.46.231

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