Structure activity relationship of cholinergic drugs and alzheimers

structure activity relationship of cholinergic drugs and alzheimers

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 STUDY OF DITERPENES FOR which could provide new leads for drugs to fight Alzheimer's disease symptoms. to restore central cholinergic function by means of acetylcholinesterase (AChE) . quinolinylamine that tetracyclic tacrine analogues, a drug currently in use for the Keywords: Tacrine analogues, AChE, structure-activity relationships, ogy of the Alzheimer's disease is the loss of cholinergic neu-.

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 ].

structure activity relationship of cholinergic drugs and alzheimers

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 ].

Alzheimer's Disease: Targeting the Cholinergic System

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 ]. 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 ]. Moreover, published data indicate that ACh is involved in memory [ 14 - 16 ]. Further studies have demonstrated that endogenous acetylcholine is important for modulation of acquisition [ 17 ], encoding [ 18 ], consolidation [ 19 ], reconsolidation [ 20 ], extinction [ 21 ] and retrieval of memory [ 22 ]. Stress is another factor that can regulate ACh release in the forebrain and its function on the hypothalamic-pituitary-adrenal HPA system can modulate biological and emotional outcomes [ 2526 ].

In a work that evaluated the function of the cholinergic system in mediating the response to stress it was found that treatment of rats with the antagonist of the nicotinic receptor, mecamylamine, attenuates the activation of the HPA axis in response to a stressor agent [ 26 ].

Alzheimer's Disease: Targeting the Cholinergic System

Similarly, nicotine can mimic the ACh effects on the HPA axis by activating nicotinic receptors [ 27 ]. Another important function of the cholinergic system is to regulate the sleep cycle [ 28 ]. It has been demonstrated that stimulation of cholinergic neurons in precise regions of the brainstem can promote REM rapid eye movement sleep, dose-dependently [ 29 ].

Moreover, ACh has many modulatory functions in the sensory cortex [ 30 - 32 ].


ACh contributes to auditory synaptic transmission by facilitating thalamo-cortical communication [ 31 ]. In addition, ACh has a function in the organization and in the neuronal response to the visual cortex [ 33 ]. Additionally, kaurenoic acid 1 presents many biological activities. For example, Kim et al reported the neuroprotective effects of a functionalized seco-ent-kauranolide CBNU06isolated from Isodon japonicus, which protected PC12 cells against a beta-induced neurotoxicity by inhibiting NF-kappaB signaling pathways, with possible beneficial effects in Alzheimer's disease.

structure activity relationship of cholinergic drugs and alzheimers

Coupling constants J are given in hertz Hz. Semisynthesis of derivatives Treatment of 1 and 4 with iodomethane 14 gave the respective methyl esters 2 and 6, with nearly quantitative yields. Compounds 13, 20 and 23 were obtained by a SN2-type reaction between 1, 19 and gibberelic acid 22respectively, and the bromolactone 5-bromomethyl 2 5H -furanone.

Compounds 24 and 25 were prepared from GA3 22 and benzyl bromide, according to Chen et al. Assay for AChE Inhibitory Activity The assays for all compounds were performed in 96 well microplates using the spectrophotometric method according to Ellman et al. To determine AChE inhibition extention, plates were read in a micro plate reader and absorbance was measured at every 60 seconds for eight times totaling eight minutes of reading.

Cholinergic - Wikipedia

A new reading was held 2 minutes AChE addition after and the absorbance measured immediately and then at every 60 seconds for nine times, totaling nine minutes of reading. Galantamine was used as a positive control. Assay was carried out in quintuplicate and absorbance was measured at nm in a microplate reader Biotec ELX