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Pharmacological Management of Alzheimer’s Disease
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rakesh Kumar, Rajan Kumar, Abhinav Anand, Neha Sharma, Navneet Khurana
Ladostigil has both neuroprotective effects cholinesterase inhibitory and monoamine oxidase MAO-A and MAO-B activities in one molecule. Ladostigil has observed about 25–40% cholinesterase inhibitor in rats. When ladostigil was administered orally at the doses range from 12–35 mg per kg it antagonizes scopolamine-induced spatial memory impairments. Ladostigil has successfully completed a preclinical study and entered in clinical trial phase II. The researchers hypothesized that an increase in the level of synaptic AChE induced by ladostigil might be one of the mode of action involved in cognitive function improvement. However, salivation, diarrhoea, and muscle weakness are the symptoms arise due to access cholinergic stimulation in the periphery until the high dose of 139 mg per kg was administered orally, which inhibited 50–60% cholinesterase. Such a wide therapeutic ratio was probably observed due to the relatively enhanced small rate in cholinesterase inhibition with increasing drug doses over the ranges of 17–69 mg per kg. This increase in cholinesterase inhibition with oral administration of ladostigil at dose 17–69 mg per kg was markedly lower and compared to subcutaneous injection of ladostigil at the doses range of 8.6–17 mg/kg; 40% increase in cholinesterase inhibition. Ladostigil was observed to inhibit both AChE and BuChE in an in vitro study. In which, the inhibitory effect was 100 times more potent against AChE than BuChE (Weinstock et al., 2000).
Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Examples of MTD already on market include inhibitors of neurotransmitter reuptake systems (SNRIs) and antagonists for combinations of receptors such the dopamine D2, serotonin 5-HT2A and α1-adrenergic receptors that can treat schizophrenia. For the brain, the main enzyme targets for recent compound discovery have been the cholinesterases (ChE) that modulate release of other neurotransmitters, the monoamine oxidases (MAO) to elevate levels of monoamines, and betasecretase 1 (BACE1) to decrease the generation of the toxic amyloid beta (Aβ) peptide. One compound that has been studied in phase 2 clinical trials for cognitive impairment is ladostigil which combines two pharmacophores taken from rivastigmine (a ChE inhibitor) and rasagiline (a propargylamine inactivator of MAO). Ladostigil inhibits acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B, and has neuroprotective effects (reviewed in Finberg and Rabey, 2016). The main dilemma in the design of multi-target drugs is choosing the correct targets, and finding the correct balance of potency for all targets in one compound in order to have the desired effect in vivo.
The pharmacotherapeutic management of postoperative delirium: an expert update
Published in Expert Opinion on Pharmacotherapy, 2020
In spite of the fact that AchE-Is have not been shown to be effective in POD treatment, the pathophysiology models of delirium highlight the acetylcholine deficits in this syndrome. Therefore, an intriguing perspective to consider in future studies is using a novel agent such as ladostigil which is an AchE-I as well as a monoamine oxidase inhibitor [128]. Although this agent was recently studied in patients with mild cognitive impairment and shown to be safe but not to delay progression to Alzheimer’s disease [129], the basic science studies in aging rats have shown that ladostigil could reduce the cascade of oxidative stress, prevent release of pro-inflammatory cytokines from activated microglia, and that cognitive deficits in episodic and spatial memory could be mitigated [130,131]. Furthermore, it has been demonstrated in a recent study in aging rats that this agent has an effect on the morphology of the microglia (in white versus gray matter), as well as ion channels important in migration, activation and secretion of pro-inflammatory cytokines depending on the brain region associated with spatial memory (parietal versus hippocampus) [132]. Therefore, given the contribution of microglia activation in the delirium hypothesis further evaluation of dosing schedules, timing of the administration of the drug, and amount of acetylcholinesterase inhibition with this agent in an appropriately selected cohort of surgical patients could be a possible study designed to prevent POD.
Developments with multi-target drugs for Alzheimer’s disease: an overview of the current discovery approaches
Published in Expert Opinion on Drug Discovery, 2019
Juan F. González, Andrés R. Alcántara, Antonio L. Doadrio, Jose María Sánchez-Montero
The therapeutic value of monoamine oxidase target has been proposed due to their confirmed neuroprotective properties; particularly, propargylamine moiety is particularly attractive because their reported neuroprotective effect already commented. Consequently, ladostigil (Figure 5) is a chimeric compound obtained by combining the neuroprotective effects of the MAO inhibitor rasagiline (dashed line box) with the carbamate moiety of the AChE inhibitor rivastigmine (full line box). Ladostigil retains the neuroprotective activities of original rasagiline and, additionally, the introduction of carbamate moiety led to brain-selective monoamine oxidase MAO-A and B inhibitory activity and increase levels of serotonin. Thus, the combination of AChE/BuChE, MAO inhibition activity and neuroprotective against oxidative stress makes ladostigil a promising useful drug for therapeutic treatment of AD. In this context, ladostigil has been licensed to Avraham Pharmaceuticals, and it is presently at phase 2 trials (NCT01354691) to evaluate ladostigil´s safety and efficacy versus placebo in mild to moderate AD patients; this study has been completed, but its results have not been made publicly available [110].
Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zofia Chrienova, Eugenie Nepovimova, Rudolf Andrys, Rafael Dolezal, Jana Janockova, Lubica Muckova, Lenka Fabova, Ondrej Soukup, Patrik Oleksak, Martin Valis, Jan Korabecny, José Marco-Contelles, Kamil Kuca
In our work we have been inspired by ladostigil (TV3326; N-propargyl-((3R)-aminoindan-5-yl)-ethyl methyl carbamate; Chart 1), a dual cholinesterase and brain-selective MAO-A and MAO-B inhibitor intended for the treatment of dementia co-morbid with extrapyramidal disorders and depression14. The rational design of this multipotent molecule is based on the combination of carbamate ChE inhibitory moiety of anti-AD drug rivastigmine (Chart 1) and N-propargyl scaffold of rasagiline (Chart 1), an anti-Parkinsonian drug and irreversible selective MAO-B inhibitor15. In rodents, oral administration of ladostigil has shown to inhibit brain ChE by 25–40% and antagonise scopolamine-induced spatial memory impairments, pointing out that it is able to penetrate the blood–brain barrier (BBB) sufficiently16. Hydrolysis of ladostigil carbamate moiety by pseudo-irreversible inhibition of ChE yields 6-hydroxyrasagiline, to which higher affinity towards both isoforms of MAO is attributed, comparing to non-hydrolyzed ladostigil17. Thus, it is most likely that an adequate concentration of 6-hydroxyrasagiline and other metabolites of ladostigil significantly inhibit MAO-A and MAO-B, increasing hereby the levels of dopamine, serotonin, and noradrenaline, which accounts for the respective anti-Parkinsonian and antidepressant properties of ladostigil18. In several studies, ladostigil has been shown to possess a broad scale of neuroprotective activities against a variety of neurotoxins and neuronal cell culture models of neurodegeneration17,19.