title: Engineered Context-Sensitive Agonism: Tissue-Selective Drug Signaling through a G Protein-Coupled Receptor.
abstract: 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.
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Wiebke K
authors.initials: WK
authors.lastname: Seemann
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Ramona
authors.initials: R
authors.lastname: Schrage
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Justine
authors.initials: J
authors.lastname: Etscheid
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Theresa
authors.initials: T
authors.lastname: Bödefeld
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Anna
authors.initials: A
authors.lastname: Bartol
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Mareille
authors.initials: M
authors.lastname: Warnken
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Philipp
authors.initials: P
authors.lastname: Sasse
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Klöckner
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Marco
authors.initials: M
authors.lastname: DeAmici
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schlicker
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Kurt
authors.initials: K
authors.lastname: Racké
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Rainer
authors.initials: R
authors.lastname: Meyer
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.) seemannwiebke@web.de bernd.fleischmann@uni-bonn.de.
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany (W.K.S., R.S., J.E., T.B., A.B., K.M.); Institute of Physiology I, Life&Brain Center, Medical Faculty, University of Bonn, Bonn, Germany (D.W., P.S., B.K.F.); Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany (M.W., E.S., K.R.); Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Würzburg, Germany (J.K., U.H.); Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica 'Pietro Pratesi,' Università degli Studi di Milano, Milano, Italy (M.D.); Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany (E.K.); Institute of Physiology II, University of Bonn, Bonn, Germany (R.M.); Center of Pharmacology, University of Cologne, Cologne, Germany (W.K.S.).
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D055808:Drug Discovery; D005260:Female; D006321:Heart / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists / Q000009:adverse effects / Q000494:pharmacology*; D043585:Receptor, Muscarinic M2 / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018721:Muscarinic Agonists; D043585:Receptor, Muscarinic M2; D000242:Cyclic AMP