Conformational studies on the four stereoisomers of the novel anticholinergic 4-(dimethylamino)-2-phenyl-2-(2-pyridyl)pentanamide.
To interpret differences in the anticholinergic activity among the four stereoisomers of 4-(dimethylamino)-2-phenyl-2-(2-pyridyl)pentanamide (1-4), we performed conformational studies using the semiempirical molecular orbital method. The structures of the global minimum-energy conformations obtained for 1-4, however, could not explain the different activities, particularly in terms of distances between the essential pharmacophores. We thus implemented superimposition studies, using the energetically stable conformations of the most active stereoisomer, 1(2S,4R), as a template. The energy penalties for a conformation change of the less active stereoisomers 2-4 from their global minimum-energy structure to a new conformation, fitting onto the global minimum-energy conformation of 1, appear to account for the differences in the pharmacological potency better than using the other conformations of 1 as a template. We thus presume that the global minimum-energy conformation of 1 is closely related to the bioactive conformation for these anticholinergics, and also that the pharmacological potency is linked to how readily these substances can change their conformations to fit the muscarinic receptor.
Oyasu
H
H
Research and Development Division, Fujisawa Pharmaceutical Company Ltd., Osaka, Japan.
Nakanishi
I
I
Tanaka
A
A
Murano
K
K
Matsuo
M
M
D000818:Animals; D018680:Cholinergic Antagonists / Q000737:chemistry*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D018680:Cholinergic Antagonists; D011725:Pyridines; C083702:vamicamide