R. Plate et al., SYNTHESIS, AND IN-VITRO AND IN-VIVO MUSCARINIC PHARMACOLOGICAL PROPERTIES OF A SERIES OF 1,6-DIHYDRO-5-(4H)-PYRIMIDINONE OXIMES, Bioorganic & medicinal chemistry, 6(9), 1998, pp. 1403-1420
A series of 1,6-dihydro-5-(4H)-pyrimidinone oxime derivatives I was sy
nthesized (Scheme 1, Tables 1 and 2) and tested for muscarinic activit
y (Table 3) in receptor binding assays using [H-3]-oxotremorine-M (Oxo
-M) and [H-3]-pirenzepine pirenzepine (Pz) as ligands. Potential musca
rinic agonistic or antagonistic properties of the compounds were deter
mined using binding studies that measured their potencies to inhibit t
he binding of Oxo-M and Pz. Preferential inhibition of Oxo-M binding w
as used as an indicator for potential muscarinic agonistic properties;
this potential was confirmed in functional studies on isolated organs
. The series produced a wide range of active compounds with differing
degrees of selectivity in M-1, M-2, and M-3 functional models. Several
compounds that have mixed agonist/antagonist profiles were able to re
duce cholinergic-related cognitive impairments in models of mnemonic f
unction. Substitutions (I, e.g. R-2 or R-3 = Me) at the 1,6-dihydro-5-
(4H)pyrimidine ring disrupted binding and efficacy, whereas systematic
variation of the oximes substituent R1 resulted in various degrees of
potency and selectivity dependent on the nature of the substitution.
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