Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor.

ABSTRACT:

Background and purpose

Artificial agonists may have higher efficacy for receptor activation than the physiological agonist. Until now, such 'superagonism' has rarely been reported for GPCRs. Iperoxo is an extremely potent muscarinic receptor agonist. We hypothesized that iperoxo is a 'superagonist'.

Experimental approach

Signalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label-free M2 muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G-protein activation, evaluation of cell surface agonist binding and computation of operational efficacies.

Key results

In CHO-hM2 cells, iperoxo significantly exceeds ACh in Gi /Gs signalling competence. In the orthosteric loss-of-function mutant M2 -Y104(3

SUBMITTER: Schrage R 

PROVIDER: S-EPMC3651662 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature