Pharmacological approaches to targeting muscarinic acetylcholine receptors

The presence of cholinergic system markers and muscarinic receptor subtypes in several tissues also of non-neuronal type has been largely demonstrated. Acetylcholine, synthesized in and out of the nervous system, can locally contribute to modulate cell proliferation, survival and apoptosis. Considering that the cholinergic system functions are impaired in a number of disorders, the identification of new drugs regulating cholinergic system functions, appears of great clinical relevance. The possible involvement of muscarinic acetylcholine receptors in different pathologies has been proposed in recent years and is becoming an important area of study. However, the lack of selective muscarinic receptor ligands has for long time limited the therapeutic treatment based on muscarinic receptors as targets. To date some muscarinic ligands such as xanomeline (patent , US5980933) or cevimeline (patents US4855290; US5571918) have been developed for the treatment of several pathologies (Alzheimer’s and Sjogren’s diseases). The present review will be focused on the potential effects produced by muscarinic receptor activation in different pathologies, including tumors. In fact, the potential use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that several muscarinic antagonists, already used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864), have also been demonstrated to arrest the tumor growth in vivo. Moreover, the contribution of muscarinic receptors to analgesia is also over-viewed. Finally, some of the most significant achievements in the field of bitopic/dualsteric ligands will be discussed and the molecules patented so far will be presented.