title: Synthesis, antimuscarinic activity and quantitative structure-activity relationship (QSAR) of tropinyl and piperidinyl esters.
abstract: 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 kw), size (molecular volume) and electronic character (Taft's polar substituent constant sigma * and 13C chemical shift difference delta delta). Finally, 92% of the M2-inhibitory activities of the esters could be accounted for by the size and electronic character sigma * of the side chain. In contrast, the M3-inhibitory activities of these esters were mainly attributed to the electronic nature (sigma *, delta delta) 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.
authors.affiliation: Department of Pharmacy, National University of Singapore, Republic of Singapore.
authors.forename: R
authors.initials: R
authors.lastname: Xu
authors.forename: M K
authors.initials: MK
authors.lastname: Sim
authors.forename: M L
authors.initials: ML
authors.lastname: Go
mesh_terms: D000818:Animals; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects*; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004952:Esters; D018727:Muscarinic Antagonists; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D014326:Tropanes; D010890:Pirenzepine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; C048593:otenzepad