New Pharmacological Approaches to the Cholinergic System: An Overview on Muscarinic Receptor Ligands and Cholinesterase Inhibitors

Abstract

The cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis. The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer’ and Sjogren’s diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice. The involvement of muscarinic receptors in nociception also is over-viewed. In fact, muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects in animal models comparable or more pronounced to those produced by morphine or opiates. Likewise, the crucial role of cholinesterases (acetylcholinesterase and butirylcholinesterase) in neural transmission is discussed, as large number of drugs inhibiting cholinesterase activity have become of increasing relevance particularly for the treatment of neurodegenerative disorders. Herein we summarize the current knowledge of the cholinesterase inhibitors with particular attention to recent patents for Alzheimer’s disease drugs.

M2muscarinic receptors inhibit cell proliferation and migration in urothelial bladder cancer cells

“…29,30 In particular, several reports have shown that M3 muscarinic receptor activation enhances tumor cell proliferation, migration and angiogenesis. 19,24,31 However 27,28 suggesting that M2 receptors might play a counteracting role in tumor cell proliferation.…”

Current and Future Issues in the Development of Spinal Agents for the Management of Pain

“…Considerable work has focused on the development of novel muscarinic agonists and cholinesterase inhibitors [293]. As noted above, there is considerable evidence that subtypes of muscarinic receptors may be involved in the spinal antinociceptive actions and anticholinesterase targeted agents.…”

Identification of two arylimides as cholinesterase inhibitors and testing of propranolol addition on impaired rat memory

“…Moreover, it has been demonstrated that the activity of this neurotransmitter in the brain is downregulated by the hydrolytic action of cholinesterases, particularly acetylcholinesterase (AChE) and also butyrylcholinesterase. Therefore, one of the main approaches for the palliative treatment of AD is still the use of AChE inhibitors (AChE-Is) (Gao, Tang, Liu, Liu, & Liu, 2019;Greig, Reale, & Tata, 2013;Herrmann, Chau, Kircanski, & Lanctôt, 2011;Hugo & Ganguli, 2014;Nygaard, 2013;Sahin et al, 2018), despite the increasing number of other strategies for treating AD that have led to drug design and development (Herrmann et al, 2011;Hugo & Ganguli, 2014;Nygaard, 2013).…”