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Treatment Of Alzheimer’s Disease
Published in Zaven S. Khachaturian, Teresa S. Radebaugh, Alzheimer’s Disease, 2019
Lina Shihabuddin, Kenneth L. Davis
Oxotremorine is a synthetic nonselective muscarinic agonist with a half-life of several hours. Oral administration of oxotremorine to Alzheimer’s disease patients did not improve cognitive function and was associated with significant side effects including depression and anxiety (Davis et al., 1987).
Parasympathomimetic Amines
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Muscarinic agonists resembling the choline esters include furtrethonium and (+)-cis-dioxolane and their methyl derivatives. They are all stable and potent non-selective full agonists. Oxotremorine and its N-methyl quaternary derivative (oxotremorine-M) are all non-selective full agonists. Oxotremorine is of interest as a research tool since it induces Parkinson’s-like central effects including tremor and ataxia. It is a tertiary amine and therefore crosses the blood-brain barrier; oxotremorine-M does not cross the blood-brain barrier and therefore has peripheral muscarinic properties only and is a more potent agonist. [3H]Oxotremorine-M is used to bind to high affinity state muscarinic receptors, thus displacement by non-labelled agents with high affinity is indicative of potent full agonist activity (eg carbachol, muscarine and methylfurtrethonium). Pilocarpine and McN-A-343 are weaker, indicating their partial agonist activity. The ratio of affinities (Kapp) for displacement of [3H]oxotremorine binding and [3H]NMS binding (low affinity antagonist binding) is high (>1,000) for full agonists such as muscarine, carbachol, oxotremorine-M, oxotremorine and methylfurtrethonium. Intermediate values are obtained for arecoline and pilocarpine, whereas values close to unity are obtained for antagonists (Freedman et al. 1988).
Secretion, Alveolar Processing, and Turnover of Pulmonary Surfactant
Published in Jacques R. Bourbon, Pulmonary Surfactant: Biochemical, Functional, Regulatory, and Clinical Concepts, 2019
As stated above, the study of the role of the autonomous nervous system in the control of surfactant release started with the observation that pilocarpine, a cholinergic agonist, was stimulatory.41 This led, in a first step, to assigning a prominent role to parasympathetic mechanisms. Subsequent observations indeed showed that cholinergic agonists, including acetylcholine, and vagal stimulation increased secretion of phosphatidylcholine and that this response could be blocked by the cholinergic antagonist atropine.21,42–44 The cholinergic muscarinic effects were, however, soon found to be indirect and exerted through adrenergic mediation. Thus, the pilocarpine-induced secretion in the artificially ventilated rat or the isolated perfused rat lung was blocked by the β-adrenergic antagonist propanolol.45 Bilateral adrenalectomy decreased by 50% the response to pilocarpine in the ventilated rat.45 Similarly, in the neonatal rabbit, the secretory effects in vivo of the cholinergic agonists oxotremorine or pilocarpine were abolished by β-adrenoreceptor antagonists.46,47 Lung isolation prevented oxotremorine stimulation, whereas epinephrine stimulus remained efficient.48 Previous adrenalectomy of the rabbit neonate also prevented the action of oxotremorine.45 Moreover, cholinergic agents were shown to be unable to stimulate secretion of surfactant components by adult rat17,21,23 as well as human49 isolated lung type II cells. Muscarinic cholinergic receptors are present in the lung,50,51 but they are most likely involved in airway tone.51,52 In type II cells, their presence is controversial. When put in direct contact with isolated type II cells, cholinergic agents appear to be able to increase intracellular cGMP,21 but the significance of this phenomenon remains unknown.
Nicotine-like discriminative stimulus effects of acetylcholinesterase inhibitors and a muscarinic receptor agonist in Rhesus monkeys
Published in Drug Development and Industrial Pharmacy, 2019
Megan J. Moerke, Lance R. McMahon
The nicotine-like discriminative stimulus effects of donepezil and galantamine, but not PNU-120596, suggest that AChE inhibition is sufficient to produce nicotine-like effects and is potentially the mechanism by which galantamine shares effects with nicotine. The current results differ from past discrimination experiments with nicotine as a training drug. For example, a prototypical AChE inhibitor physostigmine did not substitute for nicotine in rats [21]. However, there is evidence that at least some AChE inhibitors may partially generalize to the nicotine discriminative stimulus [22]. When physostigmine was trained as a discriminative stimulus, nicotine did not substitute for physostigmine and mecamylamine did not antagonize the discriminative stimulus effects of physostigmine [23]. However, oxotremorine and arecoline, both mAChR agonists, did generalize to the physostigmine discriminative stimulus [24]. AChE inhibitors can have actions at both nAChRs and mAChRs through increased endogenous ACh. This raised the possibility of a muscarinic component to the effects of some of the test drugs reported here. In fact, in the present study, the mAChR agonist oxotremorine fully substituted for the nicotine discriminative stimulus, implicating the involvement of mAChRs. Moreover, atropine antagonized the nicotine-like effects of oxotremorine as well as the discriminative stimulus effects of nicotine. Antagonism of the rate-decreasing effects of nicotine by atropine in rats has been reported previously [25]. Furthermore, atropine methyl nitrate, a peripherally restricted mAChR antagonist, was not able to antagonize these effects, providing evidence for some effect of nicotine at a central muscarinic site. The dose of atropine needed to antagonize the nicotine-like discriminative stimulus effects of oxotremorine was smaller than the dose required to antagonize the discriminative stimulus effects of nicotine. Thus, while oxotremorine and nicotine have overlapping discriminative stimulus effects involving, at least to some extent for nicotine, actions at mAChR, differential antagonism by atropine (at least quantitatively) is consistent with different underlying receptor mechanisms, perhaps reflecting the involvement of different subtypes of mAChRs in the discriminative stimulus effects of nicotine and oxotremorine. Substitution of oxotremorine for the discriminative stimulus effects of nicotine might question the validity of the current assay as a pre-clinical model to identify smoking cessations aids. Alternatively, these data could suggest that mAChRs are a potential target for the development of smoking cessation aids.