Functionally selective and biased agonists of muscarinic receptors

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 Sjogren'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 stabilise 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 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.

Automated summary

Cholinergic signalling disruption through muscarinic receptors is linked to various pathologies, with potential therapeutic benefits found in selective muscarinic agonists. The identical orthosteric binding site across all muscarinic receptor subtypes makes the development of affinity-based selective agonists nearly impossible. Functionally selective and biased agonists show promise for selectively targeting individual muscarinic receptor subtypes.