Synthesis, Antimuscarinic Activity and Quantitative Structure-Activity Relationship (QSAR) of Tropinyl and Piperidinyl Esters

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概要

• 論文の詳細を見る

• A series of tropinyl and piperidinyl esters was synthesized and evaluated for inhibitory activities on the endothelial muscarinic receptors of rat (M_3) and rabbit (M_2) aorta. Some of the esters (cyclohexylphenylglycolates and cyclohexylphenylpropionates) were found to be better antimuscarinic compounds than standard M_2 and M_3 inhibitors such as AFDX116 and 4-diphenylacetoxy-N-methylpiperidine (DAMP), with pK_<EC_<50>> values in the range of 8-9. A few esters were found to be more selective M_3 than M_2 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 σ^* and ^<13>C chemical shift difference Δδ). Finally, 92% of the M_2-inhibitory activities of the esters could be accounted for by the size and electronic character σ^* of the side chain. In contrast, the M_3-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.

• 公益社団法人日本薬学会の論文
• 1998-02-15

著者

• XU Rong

  Department of Hematology, Renji Hospital, Shanghai Jiaotong University, School of Medicine

• Xu Rong

  Department Of Hematology Renji Hospital Shanghai Jiaotong University School Of Medicine

• Xu Rong

  Department Of Pharmacy National University Of Singapore

• GO Mei-Lin

  Department of Pharmacy, National Uneversity of Sengapore

• Sim Meng-kwoon

  Department Of Pharmacology National University Of Singapore

• Go Mei-lin

  Department Of Pharmacy National University Of Singapore

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