Muscarinic acetylcholine receptors as novel therapeutic targets

The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells have been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. Acetylcholine, in fact is synthesized not only in the nervous system but also in other tissues where its local action contributes to the modulation of various cell functions (e.g. survival, proliferation). The possible involvement of acetylcholine and muscarinic receptors 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). This review will be focused on the potential implications of muscarinic receptors in the pain therapy and 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 has also been reported. 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.