Abstract
Receptor binding studies were performed on 24 soft anticholinergic agents and 5 conventional anticholinergic agents using 4 cloned human muscarinic receptor subtypes. The measured p
K
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 p
K
i
s determined here and the p
A
2
values measured earlier in guinea pig ileum contraction assays. The corresponding correlation coefficients (
r
2
) were 0.80, 0.73, 0.81, and 0.78 for p
K
i
(m
1
), p
K
i
(m
2
), p
K
i
(m
3
), and p
K
i
(m
4
), 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 p
K
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 p
K
i
(m
3
) values.
