PT  - JOURNAL ARTICLE
AU  - Seemann, Wiebke K.
AU  - Wenzel, Daniela
AU  - Schrage, Ramona
AU  - Etscheid, Justine
AU  - Bödefeld, Theresa
AU  - Bartol, Anna
AU  - Warnken, Mareille
AU  - Sasse, Philipp
AU  - Klöckner, Jessica
AU  - Holzgrabe, Ulrike
AU  - DeAmici, Marco
AU  - Schlicker, Eberhard
AU  - Racké, Kurt
AU  - Kostenis, Evi
AU  - Meyer, Rainer
AU  - Fleischmann, Bernd K.
AU  - Mohr, Klaus
TI  - Engineered Context-Sensitive Agonism: Tissue-Selective Drug Signaling through a G Protein-Coupled Receptor
AID  - 10.1124/jpet.116.237149
DP  - 2017 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 289--299
VI  - 360
IP  - 2
4099  - http://jpet.aspetjournals.org/content/360/2/289.short
4100  - http://jpet.aspetjournals.org/content/360/2/289.full
SO  - J Pharmacol Exp Ther2017 Feb 01; 360
AB  - Drug discovery strives for selective ligands to achieve targeted modulation of tissue function. Here we introduce engineered context-sensitive agonism as a postreceptor mechanism for tissue-selective drug action through a G protein-coupled receptor. Acetylcholine M2-receptor activation is known to mediate, among other actions, potentially dangerous slowing of the heart rate. This unwanted side effect is one of the main reasons that limit clinical application of muscarinic agonists. Herein we show that dualsteric (orthosteric/allosteric) agonists induce less cardiac depression ex vivo and in vivo than conventional full agonists. Exploration of the underlying mechanism in living cells employing cellular dynamic mass redistribution identified context-sensitive agonism of these dualsteric agonists. They translate elevation of intracellular cAMP into a switch from full to partial agonism. Designed context-sensitive agonism opens an avenue toward postreceptor pharmacologic selectivity, which even works in target tissues operated by the same subtype of pharmacologic receptor.