title: Synthesis, and in vitro and in vivo muscarinic pharmacological properties of a series of 1,6-dihydro-5-(4H)-pyrimidinone oximes.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, N. V. Organon, Oss, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Plate
authors.forename: M J
authors.initials: MJ
authors.lastname: Plaum
authors.forename: P
authors.initials: P
authors.lastname: Pintar
authors.forename: C G
authors.initials: CG
authors.lastname: Jans
authors.forename: T
authors.initials: T
authors.lastname: de Boer
authors.forename: F A
authors.initials: FA
authors.lastname: Dijcks
authors.forename: G
authors.initials: G
authors.lastname: Ruigt
authors.forename: J S
authors.initials: JS
authors.lastname: Andrews
mesh_terms: 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
chemical_list: D018678:Cholinergic Agents; D010091:Oximes