Receptor binding studies of soft anticholinergic agents.
Receptor binding studies were performed on 24 soft anticholinergic agents and 5 conventional anticholinergic agents using 4 cloned human muscarinic receptor subtypes. The measured pK(i) values of the soft anticholinergic agents ranged from 6.5 to 9.5, with the majority being in the range of 7.5 to 8.5. Strong correlation was observed between the pK(i) s determined here and the pA 2 values measured earlier in guinea pig ileum contraction assays. The corresponding correlation coefficients (r2) were 0.80, 0.73, 0.81, and 0.78 for pK(i) (m1), pK(i) (m2), pK(i) (m3), and pK(i) (m4), respectively. Quantitative structure-activity relationship (QSAR) studies were also performed, and good characterization could be obtained for the soft anticholinergics containing at least 1 tropine moiety in their structure. For these compounds, the potency as measured by the pK i values was found to be related to geometric, electronic, and lipophilicity descriptors. A linear regression equation using ovality (O(e)), dipole moment (D), and a calculated log octanol-water partition coefficient (QLogP) gave reasonably good descriptions (r = 0.88) for the pK(i) (m3) values.
Huang
F
F
Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville, FL 32610-0497, USA.
Buchwald
P
P
Browne
C E
CE
Farag
H H
HH
Wu
W M
WM
Ji
F
F
Hochhaus
G
G
Bodor
N
N
D000818:Animals; D018680:Cholinergic Antagonists / Q000138:chemical synthesis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000737:chemistry; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011976:Receptors, Muscarinic / Q000378:metabolism*
D018680:Cholinergic Antagonists; D011976:Receptors, Muscarinic