Synthesis, and in vitro and in vivo muscarinic pharmacological properties of a series of 1,6-dihydro-5-(4H)-pyrimidinone oximes.
A series of 1,6-dihydro-5-(4H)-pyrimidinone oxime derivatives I was synthesized (Scheme 1, Tables 1 and 2) and tested for muscarinic activity (Table 3) in receptor binding assays using [3H]-oxotremorine-M (Oxo-M) and [3H]-pirenzepine (Pz) as ligands. Potential muscarinic agonistic or antagonistic properties of the compounds were determined using binding studies that measured their potencies to inhibit the binding of Oxo-M and Pz. Preferential inhibition of Oxo-M binding was 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 M1, M2, and M3 functional models. Several compounds that have mixed agonist/antagonist profiles were able to reduce cholinergic-related cognitive impairments in models of mnemonic function. Substitutions (I, e.g. R2 or R3 = 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.
Plate
R
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Department of Medicinal Chemistry, N. V. Organon, Oss, The Netherlands.
Plaum
M J
MJ
Pintar
P
P
Jans
C G
CG
de Boer
T
T
Dijcks
F A
FA
Ruigt
G
G
Andrews
J S
JS
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D018678:Cholinergic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004558:Electric Stimulation; D004569:Electroencephalography; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D018678:Cholinergic Agents; D010091:Oximes