Design and development of selective muscarinic agonists for the treatment of Alzheimer's disease: characterization of tetrahydropyrimidine derivatives and development of new approaches for improved affinity and selectivity for M1 receptors

The utility of muscarinic agonists in the treatment of alzheimer’s disease

“…Animals treated with 192 IgG saporin had approx 50% lower levels of ChATase activity in the cerebral cortex and hippocampus as compared to vehicle-injected controls, indicating a loss of cholinergic neurons (data not shown). At 1.0 mg/kg i.p., both xanomeline and CDD-0102 reversed memory deficits associated with a loss of basal forebrain cholinergic neurons (Messer et al, 2000). At this dose, xanomeline produced diarrhea, while animals treated with CDD-0102 exhibited only a slight softening of the stool.…”

“…The novel amidine derivatives exhibit excellent agonist activity at M 1 receptors expressed in cell lines and in brain, and very low activity at M 3 receptors Messer et al, 2000). In particular, 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine (CDD-0102) has emerged as a potent M 1 agonist with a low side-effect profile.…”

Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists

“…All three compounds, at doses comparable to or less than xanomeline, effectively reverse the cognitive impairment induced by nucleus basalis lesions in rodents (Wanibuchi et al 1994;Messer et al 2000;Tecle et al 2000) (see Table 3 for comparisons). Moreover, these drugs appear superior to xanomeline in that effects on M 3 mediated processes such as salivation and GI motility occur at doses much higher than the doses required to reverse memory deficits (Wanibuchi et al 1994;Messer et al 2000;Tecle et al 2000) (see Table 3 for comparisons). Although early in their development these compounds seem to have promising cognitive enhancing and antipsychotic potential in the treatment of schizophrenia.…”

Identification of miRNAs in C. roseus and their potential targets

“…cath-miR 2 hybridizes with CHRM1, HM1, M1R and MGC30125 genes that are responsible for mediating slow excitory post synaptic potential at postganglionic nerve [33]. PARVG gene hybridized by cath-miRNA 3 is responsible for coding Parvin protein (are actin binding protein found to be associated with focal contacts) [34], cath miRNA 4 was found to be responsible for silencing various signal transducting and apoptotic genes.…”