title: Surface modified nano-lipid drug conjugates of positive allosteric modulators of M1 muscarinic acetylcholine receptor for the treatment of Alzheimer's disease.
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 M1muscarinic 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 M2-M5muscarinic subtypes in various tissues. It is logical, therefore, to develop agonists with M1receptor 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 M1receptors 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 M1receptors 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.
authors.affiliation: Department of Pharmacology, JSS College of Pharmacy, (A Constituent of JSS University Mysore), Ootacamund, Tamil Nadu 643001, India.
authors.forename: Pavan Kumar
authors.initials: PK
authors.lastname: Chintamaneni
authors.affiliation: Department of Pharmacology, JSS College of Pharmacy, (A Constituent of JSS University Mysore), Ootacamund, Tamil Nadu 643001, India. Electronic address: praveentk7812@gmail.com.
authors.forename: Praveen T
authors.initials: PT
authors.lastname: Krishnamurthy
authors.affiliation: Department of Pharmacology, JSS College of Pharmacy, (A Constituent of JSS University Mysore), Ootacamund, Tamil Nadu 643001, India.
authors.forename: Pachava Vengal
authors.initials: PV
authors.lastname: Rao
authors.affiliation: Department of Pharmacology, JSS College of Pharmacy, (A Constituent of JSS University Mysore), Ootacamund, Tamil Nadu 643001, India.
authors.forename: SaiKiran S S
authors.initials: SS
authors.lastname: Pindiprolu
mesh_terms: D000109:Acetylcholine / Q000737:chemistry; D000495:Allosteric Site; D000544:Alzheimer Disease / Q000628:therapy*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D000077265:Donepezil; D016503:Drug Delivery Systems; D005786:Gene Expression Regulation; D006801:Humans; D007189:Indans / Q000627:therapeutic use; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008962:Models, Theoretical; D058726:Nanoconjugates / Q000737:chemistry*; D050997:Nanomedicine; D010316:Particle Size; D010766:Phosphorylation; D010880:Piperidines / Q000627:therapeutic use; D058225:Plaque, Amyloid / Q000378:metabolism; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors*; D013499:Surface Properties
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D008024:Ligands; D008055:Lipids; D058726:Nanoconjugates; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D000077265:Donepezil; D000109:Acetylcholine
keywords: Alzheimer’s disease; Blood brain barrier; Lipid drug conjugates; Positive allosteric modulators