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Surface modified nano-lipid drug conjugates of positive allosteric modulators of M1 muscarinic acetylcholine receptor for the treatment of Alzheimer's disease.
- Source :
-
Medical hypotheses [Med Hypotheses] 2017 Apr; Vol. 101, pp. 17-22. Date of Electronic Publication: 2017 Feb 09. - Publication Year :
- 2017
-
Abstract
- Acetyl Cholinesterase (AChE) inhibitors such as Donepezil, Rivastigmine and Galantamine are approved by US-FDA as first line drugs to treat the cognitive symptoms of Alzheimer's disease (AD). Their beneficial effects are attributed to their ability to elevate endogenous acetylcholine (ACh) at the M <subscript>1</subscript> muscarinic receptor in the brain. However, their side effects such as nausea, vomiting, dizziness, insomnia, loss of appetite and altered heart rate are related to non-specific activation of M <subscript>2</subscript> -M <subscript>5</subscript> muscarinic subtypes in various tissues. It is logical, therefore, to develop agonists with M <subscript>1</subscript> receptor selectivity. Unfortunately, this is limited due to a high degree of orthosteric site homology among the receptor subtypes. In contrast, their allosteric sites are unique and, therefore, allow selective targeting using positive allosteric modulators (PAMs). PAMs of M <subscript>1</subscript> receptors are devoid of agonist activity, however, when bound they enhance the binding affinity of orthosteric ligand, ACh. The major limitation of these PAMs is their bioavailability in the brain. In the current hypothesis, we propose surface modified nano-lipid drug conjugates (LDC-NPs) of PAMs of M <subscript>1</subscript> receptors to improve their bioavailability in brain. When co-administered with AChE inhibitors they are expected to increase their efficacy and reduce their therapeutic dose and side effects.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- Acetylcholine chemistry
Allosteric Site
Animals
Blood-Brain Barrier
Brain drug effects
Donepezil
Gene Expression Regulation
Humans
Indans therapeutic use
Ligands
Lipids chemistry
Mice
Models, Theoretical
Nanomedicine
Particle Size
Phosphorylation
Piperidines therapeutic use
Plaque, Amyloid metabolism
Surface Properties
Alzheimer Disease therapy
Cholinesterase Inhibitors therapeutic use
Drug Delivery Systems
Nanoconjugates chemistry
Receptor, Muscarinic M1 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1532-2777
- Volume :
- 101
- Database :
- MEDLINE
- Journal :
- Medical hypotheses
- Publication Type :
- Academic Journal
- Accession number :
- 28351483
- Full Text :
- https://doi.org/10.1016/j.mehy.2017.01.026