title: Quantitative structure-selectivity relationship for M2 selectivity between M1 and M2 of piperidinyl piperidine derivatives as muscarinic antagonists.
abstract: Muscarinic M2 receptor antagonists with high subtype selectivity (M2/M1) will decrease the toxicity in central nervous system in treatment of AD. The exploration of quantitative structure-selectivity relationship (QSSR) to muscarinic M2 receptor antagonists will provide design information for drug with fewer side effects. In this paper, CoMFA models of pK(i)(M1), pK(i)(M2) and p[K(i)(M2)/K(i)(M1)] (pK(i)(M2)-pK(i)(M1)) were used to study the subtype selectivity (M2/M1) of piperidinyl piperidine derivatives as muscarinic M2 subtype receptor antagonists. The parameters of the three models are: 0.633, 0.636 and 0.726 for cross-validated r(2) (r(cv)(2)), 0.109, 0.204 and 0.09 for the Standard error of estimate (SD), respectively. The results show the model of p[K(i)(M2)/K(i)(M1)] is the best one for design of piperidinyl piperidine derivatives as muscarinic antagonists with high subtype selectivity (M2/M1).
authors.affiliation: Department of Pharmacy, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yin-Yao
authors.initials: YY
authors.lastname: Niu
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Yang
authors.forename: Ke-Min
authors.initials: KM
authors.lastname: Deng
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Yao
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.forename: Cong-Ying
authors.initials: CY
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Jin-E
authors.initials: JE
authors.lastname: Zhou
authors.forename: Tian-Xiang
authors.initials: TX
authors.lastname: Shen
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D015195:Drug Design; D006801:Humans; D018727:Muscarinic Antagonists / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D043643:Receptor, Muscarinic M1 / Q000187:drug effects; D043585:Receptor, Muscarinic M2 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D018727:Muscarinic Antagonists; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2