1-Alkyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-alkyl-oximes: a new class of potent orally active muscarinic agonists related to arecoline

Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry

“…Further, the functional potency and selectivity of the agonists were compared with their radioligand binding affinity at the cloned muscarinic receptors in the same cell lines. The agonists studied have been claimed to show functional selectivity in in vitro and in vivo models for the M 1 receptor, such as xanomeline ( Shannon et al ., 1994 ), milameline ( Toja et al ., 1991 ) and sabcomeline (SB 202026, Loudon et al ., 1997 ). It was therefore important to determine whether this functional selectivity was reflected in selectivity for cloned muscarinic receptor subtypes.…”

Milameline: Nonselective, Partial Muscarinic Receptor Agonist for the Treatment of Alzheimer's Disease?

“…All animals were observed for 1 w after treatment. The median lethal dose (LD 50 ) was 600 mg/kg in mice and 300 mg/kg in rats (41). These doses were about 10 2 -10 3 higher than those required for overt central effects ( Table 2).…”

“…Peripheral adverse effects appeared to be diminished with the repeated administration of the drug, while its central cholinergic efficacy was maintained (6,36). Toja et al (41) were first to report that oral milameline alleviated scopolamine-induced memory deficits in mice ( Table 2). Memory enhancing effects were measured with the one-trial passive-avoidance task, which is accepted as a measure of reference memory (23).…”

Molecular Variations Based on Isosteric Replacements

“…Worth noting is the successful replacement of the methyl ester with oxime ethers and N-methoxy imidoyl nitrile in the design of muscarinic agonists (Figure 8.28) [131,132].…”