Agonists with supraphysiological efficacy at the muscarinic M2 ACh receptor. (25th April 2013)

• Record Type: Journal Article
• Authors: Schrage, R; Seemann, WK; Klöckner, J; Dallanoce, C; Racké, K; Kostenis, E; De Amici, M; Holzgrabe, U; Mohr, K
• Is Part Of: British journal of pharmacology. Volume 169:Number 2(2013:May)
• Page Start: 357
• Page End: 370
• Publication Date: 2013-04-25
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12003
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12003-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>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'.</p> </sec> <sec id="bph12003-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>Signalling of iperoxo and newly synthesized structural analogues was compared with that of ACh at label‐free M<sub>2</sub> muscarinic receptors applying whole cell dynamic mass redistribution, measurement of G‐protein activation, evaluation of cell surface agonist binding and computation of operational efficacies.</p> </sec> <sec id="bph12003-sec-0003" sec-type="section"> <title>Key Results</title> <p>In CHO‐hM<sub>2</sub> cells, iperoxo significantly exceeds ACh in G<sub>i</sub>/G<sub>s</sub> signalling competence. In the orthosteric loss‐of‐function mutant M<sub>2</sub>‐Y104<sup>3.33</sup>A, the maximum effect of iperoxo is hardly compromised in contrast to ACh. 'Superagonism' is preserved in the physiological cellular context of MRC‐5 human lung fibroblasts. Structure–signalling relationships including iperoxo derivatives with either modified positively charged head group or altered tail suggest that 'superagonism' of iperoxo is mechanistically based on parallel activation of the receptor protein via two orthosteric interaction points.</p> </sec> <sec id="bph12003-sec-0004" sec-type="section"> <title>Conclusion and Implications</title> <p>Supraphysiological agonist efficacy at muscarinic M<sub>2</sub> ACh receptors is demonstrated for the first time. In addition, a possible underlying molecular mechanism of GPCR 'superagonism' is provided. We suggest that iperoxo‐like orthosteric GPCR activation is a new avenue towards a novel class of receptor activators.</p> </sec> <sec id="bph12003-sec-1001" sec-type="relatedArticles"> <title>Linked Article</title> <p>This article is commented on by Langmead and Christopoulos, pp. 353–356 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12142</p> </sec> </abstract>