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Functionally selective and biased agonists of muscarinic receptors.

Functionally selective and biased agonists of muscarinic receptors. Biased signaling at muscarinic receptors

Randáková, A.; Jakubík, J. Functionally Selective and Biased Agonists of Muscarinic Receptors. Pharmacol. Res. 2021, 169, 105641, doi:10.1016/j.phrs.2021.105641.

Invited review.

Disruption of cholinergic signalling via muscarinic receptors is associated with various pathologies, like Alzheimer's disease or schizophrenia. Selective muscarinic agonists possess therapeutic potential in the treatment of diabetes, pain or Sjögren's syndrome. The orthosteric binding site of all subtypes of the muscarinic receptor is structurally identical, making the development of affinity-based selective agonists virtually impossible. Some agonists, however, are functionally selective; they activate only a subset of receptors or signalling pathways. Others may stabilize specific conformations of the receptor leading to non-uniform modulation of individual signalling pathways (biased agonists). Functionally selective and biased agonists represent a promising approach for the selective activation of individual subtypes of muscarinic receptors. In this work, we review chemical structures, receptor binding and agonist-specific conformations of currently known functionally selective and biased muscarinic agonists in the context of their intricate intracellular signalling. Further, we take a perspective on the possible use of biased agonists for tissue and organ-specific activation of muscarinic receptors.