QSAR and molecular modelling of antimuscarinic 7-amino-1-hydroxy-5-heptyn-2-ones.
A profile of antimuscarinic response and its duration of action of substituted 7-amino-1-hydroxy-5-heptyn-2-ones can be correlated against the molecular space, partial energy of the nitrogen atom of the side chain, and the STERIMOL parameters maximum width and length. The molecules are conformationally rigid in the low-energy state which seems to be condition for specific interactions with accessory binding sites of the muscarinic M3 receptor. The agents can be activated energetically to more flexible compounds which may favor covalent binding to the catalytic center of the M3 receptor. On the basis of the results obtained, a common pharmacophore of three structurally diverse classes of M3 antagonists is proposed. The matrix of optimized Cartesian coordinates of a molecule can be transformed to a vector-valued observation which can be applied to develop quantitative conformation-activity relationships.
Institute of Pharmacology and Toxicology of the University, Leipzig, Germany.
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D000480:Alkynes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006168:Guinea Pigs; D008333:Mandelic Acids / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D018727:Muscarinic Antagonists; D010276:Parasympatholytics / Q000737:chemistry / Q000494:pharmacology*; D012044:Regression Analysis; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000480:Alkynes; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; C005419:oxybutynin