Structure activity relationship of cholinergic drugs and alzheimers

Alzheimer's Disease: Targeting the Cholinergic System

structure activity relationship of cholinergic drugs and alzheimers

improvement in the cognitive function of Alzheimer's patients. theory, six classes of drugs have been developed to enhance cholinergic deficit in AD patient. STRUCTURAL ACTIVITY RELATIONSHIP AMONG THE CHOLINERGIC AND - A cholinergic drug is a drug that acts on the peripheral nervous system, the central nervous •Used in the treatment of mild to moderate Alzheimer's disease . Thus, drugs that act on the cholinergic system represent a promising option to treat AD .. Distinct types of nicotinic receptors are expressed in various structures, .. of rat brain choline acetyltransferase and its relationship to enzyme activity.

structure activity relationship of cholinergic drugs and alzheimers

ACh is the neurotransmitter used by all cholinergic neurons, which has a very important role in the peripheral and central nervous systems. All pre- and post-ganglionic parasympathetic neurons and all pre-ganglionic sympathetic neurons use ACh as neurotransmitter. In addition, part of the post-ganglionic sympathetic neurons also uses ACh as neurotransmitter.

In the central nervous system CNSthe cholinergic neurons are widely distributed [ 23 ]. They are mainly found in the spinal cord, hindbrain, medial habenula, mesopontine region, basal forebrain, striatum, olfactory tubercle and islands of Cajella complex [ 24 - 7 ]. Almost all regions of the brain are innervated by cholinergic neurons [ 3 ].

Cholinergic system during the progression of Alzheimer's disease: therapeutic implications

Given its widespread distribution in the brain, it is not surprising that cholinergic neurotransmission is responsible for modulating important neural functions. The cholinergic system is involved in critical physiological processes, such as attention, learning, memory, stress response, wakefulness and sleep, and sensory information. Experimental data using non-human primates and rodents have demonstrated that injuries introduced to basal forebrain cholinergic neurons that innervate the cortex lead to attention deficit [ 89 ].

structure activity relationship of cholinergic drugs and alzheimers

On the other hand, the facilitation of the cholinergic transmission by using the cholinesterase inhibitors can improve attention in humans [ 1011 ]. It has been demonstrated that the cholinergic system plays a role in the learning process [ 1213 ].

Cholinergic system during the progression of Alzheimer's disease: therapeutic implications

Moreover, published data indicate that ACh is involved in memory [ 14 - 16 ]. Without advances in rational drug therapy for the treatment of dementia, the number of symptomatic cases in the USA is predicted to reach 13 million by These data highlight the immediacy of developing more effective therapeutic interventions for those in the early or prodromal stages of AD.

structure activity relationship of cholinergic drugs and alzheimers

Prodromal AD Although AD is a progressive neurodegenerative disorder characterized clinically by irreversible cognitive deterioration, evidence suggests that mild cognitive impairment MCI is one of the most common conditions affecting persons over the age of 65 years, and that the prevalence for MCI is more than double that of dementia.

People with a clinical diagnosis of MCI comprise a heterogeneous cohort of which those with memory deficits only are classified as amnestic MCI aMCI and those with impairment in other cognitive domains lacking a clinical diagnosis of dementia are designated multi-domain MCI mdMCI [ 34 ]. Many individuals characterized with aMCI progress steadily to greater stages of dementia severity, and in many instances exhibit the neuropathologic, molecular and biochemical hallmarks of AD [ 5 - 9 ].

structure activity relationship of cholinergic drugs and alzheimers

These clinical pathobiologic studies suggest that MCI, in general, represents a prodromal or preclinical stage of AD. Since it is believed that AD has an extensive preclinical phase, understanding the molecular pathogenesis leading to AD will require studying people during the early stages of the disease when brain pathology has been initiated prior to presentation of significant clinical symptoms [ 10 ].

The current review will highlight research directed at understanding the neuropathobiology of well-characterized cholinergic deficits seen in patients with AD, with emphasis on molecular and cellular alterations early in the disease process, and how these findings translate to potential drug treatments for dementia.

Cholinergic basal forebrain system Although there is a widespread decline in various neurotransmitter-containing cell bodies in end-stage AD, the most consistent losses throughout the progression of AD are seen in long projection neurons, including cholinergic neurons of the basal forebrain [ 11 - 13 ]. Cholinergic neurons within the nucleus basalis NB and the septal diagonal band complex provide the major source of cholinergic innervation to the cerebral cortex and hippocampus, respectively, and play a key role in memory and attentional function [ 11 - 13 ].

Cholinergic basal forebrain CBF cortical projection neurons contain the pathological AD hallmark, neurofibrillary tangles NFTsand undergo chemical phenotypic alterations during the progression of AD, making them an excellent natural model for studying mechanisms of cell death, survival and treatment approaches both in vitro and in vivo, including relevant animal models of neurodegeneration as well as human postmortem clinical pathological tissue studies [ 14 ].

The regions of the forebrain that contain cholinobasal and septohippocampal CBF neurons also display various non-cholinergic neurons, including GABAergic interneurons that innervate cholinergic perikarya [ 11 ]. In addition, neuropeptides often co-localize with CBF neurons.

  • Services on Demand
  • Navigation menu
  • Alzheimer's disease

Therefore, it is likely that neurotransmitter interactions may provide novel targets for the development of modulatory polypharmaceutical treatment approaches for cholinergic deficits seen in AD see later. Cholinergic dysfunction in AD The loss of cholinergic markers within vulnerable neurons and their respective projection sites has been a major tenet in AD research for over 30 years. Specifically, progressive phenotypic downregulation of markers within CBF neurons as well as frank CBF cell loss has been observed consistently, along with an associated reduction of choline acetyltransferase ChAT and acetylcholinesterase AChE activity within the cortex in AD [ 16 ].

Most researchers presumed that progressive disruption of cholinergic function underlies much of the short-term memory loss seen in AD. Kaurane diterpenes are a class of natural products available in large amounts in nature and isolated from plants grown worldwide.

The kaurenoic acid derivatives screened showed to be promising inhibitors of AChE, which could provide new leads for drugs to fight Alzheimer's disease symptoms. Among them, eleven compounds showed activities comparable or higher than the positive control galantamine. Existence of an allylic hydroxyl group showed to be an important structural feature for AChE inhibition.

structure activity relationship of cholinergic drugs and alzheimers

In addition, presence of free hydroxyl groups at C and C, furnished a diol especially active, able to completely inhibit AChE.

It is growing more and more with the increase in life expectancy, being irreversible, degenerative and age-related. This disease is characterized by accumulation of senile plaques, which has beta-amyloid as its major constituent.