10.1002/cmdc.201900283
ChemMedChem
COMMUNICATION
[13] A. Bock; R. Schrage; K. Mohr, Neuropharmacology 2018, 136,
427-437.
Different to findings published earlier with other non-agonistically
active BQCAd building blocks,20 in the current study spacer
lengths smaller than C5 resulted in partially active BQCAd
moieties thus contributing to the orthosteric agonistic effect of the
carbachol moiety. Nevertheless, the BQCAd moiety 25b (which
includes a C5 spacer) of the BQCAd-carbachol-hybrid 2b
possessing the highest efficacy (and potency) did not contribute
to M1-receptor activation. This demonstrates that the carbachol
moiety pertained part of its agonistic action in this hybrid.
Inversely, the orthosteric carbachol massively quenched M1-
receptor activation in the bitopic TBPBd-carbachol-hybrid 1b to a
marginal partial agonism at a high concentration compared to its
TBPBd-C5 moiety which behaved as a full agonist. In summary,
in the current study, we demonstrate that partial agonism in
dualsteric/bitopic compounds can be designed not only by
quenching orthosteric receptor activation by an allosteric moiety
as in 2b but also by quenching putative bitopic/dualsteric
activation of the receptor protein by an orthosteric moiety such as
carbachol in 1b. These findings practically widen the effect of
orthosteric moieties in the concept of putative dualsteric/bitopic
ligands. They allow different extents of partial agonism and
furthermore enlarge the molecular toolbox of hybrid ligands to
investigate mAChR receptor function. More advanced studies
with regard to signaling bias and subtype selectivity are ongoing.
[14] A. E. Davey; K. Leach; C. Valant; A. D. Conigrave; P. M. Sexton;
A. Christopoulos, Endocrinology 2012, 153, 1232-1241.
[15] A. Christopoulos; J. P. Changeux; W. A. Catterall; D. Fabbro; T.
P. Burris; J. A. Cidlowski; R. W. Olsen; J. A. Peters; R. R. Neubig; J.
P. Pin; P. M. Sexton; T. P. Kenakin; F. J. Ehlert; M. Spedding; C. J.
Langmead, Pharmacol. Rev. 2014, 66, 918-947.
[16] K. Mohr; J. Schmitz; R. Schrage; C. Tränkle; U. Holzgrabe,
Angew. Chem. Int. Ed. 2013, 52, 508-516.
[17] A. Bock; N. Merten; R. Schrage; C. Dallanoce; J. Batz; J.
Klöckner; J. Schmitz; C. Matera; K. Simon; A. Kebig; L. Peters; A.
Muller; J. Schrobang-Ley; C. Tränkle; C. Hoffmann; M. De Amici; U.
Holzgrabe; E. Kostenis; K. Mohr, Nat. Commun. 2012, 3, 1044.
[18] B. J. Davie; A. Christopoulos; P. J. Scammells, ACS Chem.
Neurosci. 2013, 4, 1026-1048.
[19] J. Antony; K. Kellershohn; M. Mohr-Andrä; A. Kebig; S. Prilla; M.
Muth; E. Heller; T. Disingrini; C. Dallanoce; S. Bertoni; J. Schrobang;
C. Tränkle; E. Kostenis; A. Christopoulos; H. D. Höltje; E. Barocelli;
M. De Amici; U. Holzgrabe; K. Mohr, FASEB J. 2009, 23, 442-450.
[20] X. Chen; J. Klöckner; J. Holze; C. Zimmermann; W. K. Seemann;
R. Schrage; A. Bock; K. Mohr; C. Tränkle; U. Holzgrabe; M. Decker,
J. Med. Chem. 2015, 58, 560-576.
[21] L. Agnetta; M. Bermudez; F. Riefolo; C. Matera; E. Claro; R.
Messerer; T. Littmann; G. Wolber; U. Holzgrabe; M. Decker, J. Med.
Chem. 2019, 62, 3009-3020.
[22] L. Agnetta; M. Kauk; M. C. A. Canizal; R. Messerer; U. Holzgrabe;
C. Hoffmann; M. Decker, Angew. Chem. Int. Ed. 2017, 56, 7282-7287.
[23] R. Messerer; C. Dallanoce; C. Matera; S. Wehle; L. Flammini; B.
Chirinda; A. Bock; M. Irmen; C. Trankle; E. Barocelli; M. Decker; C.
Sotriffer; M. De Amici; U. Holzgrabe, Med. Chem. Commun. 2017, 8,
1346-1359.
[24] R. Messerer; M. Kauk; D. Volpato; M. C. Alonso Canizal; J.
Klockner; U. Zabel; S. Nuber; C. Hoffmann; U. Holzgrabe, ACS Chem.
Biol. 2017, 12, 833-843.
[25] P. I. Kitov; H. Shimizu; S. W. Homans; D. R. Bundle, J. Am.
Chem. Soc. 2003, 125, 3284-3294
Experimental Section
Synthetic procedures and conducted assay procedures are found
in the supporting information.
[26] M. Bermudez; C. Rakers; G. Wolber, Mol. Inform. 2015, 34, 526-
530.
[27] M. Bermudez; A. Bock; F. Krebs; U. Holzgrabe; K. Mohr; M. J.
Lohse; G. Wolber, ACS Chem. Biol. 2017, 12, 1743-1748.
[28] K. M. Sanders; M. H. Zhu; F. Britton; S. D. Koh; S. M. Ward, Exp.
Physiol. 2012, 97, 200-206.
[29] C. K. Jones; A. E. Brady; A. A. Davis; Z. Xiang; M. Bubser; M. N.
Tantawy; A. S. Kane; T. M. Bridges; J. P. Kennedy; S. R. Bradley; T.
E. Peterson; M. S. Ansari; R. M. Baldwin; R. M. Kessler; A. Y. Deutch;
J. J. Lah; A. I. Levey; C. W. Lindsley; P. J. Conn, J. Neurosci. 2008,
28, 10422-10433.
[30] S. J. Bradley; C. Molloy; C. Bundgaard; A. J. Mogg; K. J.
Thompson; L. Dwomoh; H. E. Sanger; M. D. Crabtree; S. M. Brooke;
P. M. Sexton; C. C. Felder; A. Christopoulos; L. M. Broad; A. B. Tobin;
C. J. Langmead, Mol. Pharmacol. 2018, 93, 645-656.
[31] A. Christopoulos, Mol. Pharmacol. 2014, 86, 463-478.
[32] A. Fisher, Jpn. J. Pharmacol. 2000, 84, 101-112.
[33] A. Fisher; R. Brandeis; R. H. N. Bar-Ner; M. Kliger-Spatz; N.
Natan; H. Sonego; I. Marcovitch; Z. Pittel, J. Mol. Neurosci. 2002, 19,
145-153.
Acknowledgments
Generous support by the Elite Network of Bavaria (ENB) and
International Doctoral Program “Receptor Dynamics” for L.A., H.
G. and T.L. is gratefully aknowledged.
Keywords: Muscarinic Receptor • GPCR • Dualsteric Ligands •
Partial Agonism • Allostery
References
[1] A. C. Kruse; B. K. Kobilka; D. Gautam; P. M. Sexton; A.
Christopoulos; J. Wess, Nat. Rev. Drug Discov. 2014, 13, 549-560.
[2] R. M. Eglen; A. Choppin; N. Watson, Trends Pharmacol. Sci. 2001,
22, 409-414.
[3] A. Sanabria-Castro; I. Alvarado-Echeverria; C. Monge-Bonilla,
Ann. Neurosci. 2017, 24, 46-54.
[34] M. Decker; U. Holzgrabe, Med. Chem. Commun. 2012, 3, 752-
762.
[35] M. Canals; J. R. Lane; A. Wen; P. J. Scammells; P. M. Sexton;
A. Christopoulos, J. Biol. Chem. 2012, 287, 650-659.
[36] J. K. Shirey; A. E. Brady; P. J. Jones; A. A. Davis; T. M. Bridges;
J. P. Kennedy; S. B. Jadhav; U. N. Menon; Z. Xiang; M. L. Watson; E.
P. Christian; J. J. Doherty; M. C. Quirk; D. H. Snyder; J. J. Lah; A. I.
Levey; M. M. Nicolle; C. W. Lindsley; P. J. Conn, J. Neurosci. 2009,
29, 14271-14286.
[4] R. T. Bartus, Exp. Neurol. 2000, 163, 495-529.
[5] R. M. Eglen, Prog. Med. Chem. 2005, 43, 105-136.
[6] A. Fisher, Neurotherapeutics 2008, 5, 433-442.
[7] A. Fisher, Neurodegener. Dis. 2008, 5, 237-240.
[8] A. Fisher, Curr. Alzheimer Res. 2007, 4, 577-580.
[9] A. Fisher, J. Neurochem. 2012, 120, 22-33.
[37] L. Ma; M. A. Seager; M. Wittmann; M. Jacobson; D. Bickel; M.
Burno; K. Jones; V. K. Graufelds; G. Xu; M. Pearson; A. McCampbell;
R. Gaspar; P. Shughrue; A. Danziger; C. Regan; R. Flick; D.
Pascarella; S. Garson; S. Doran; C. Kreatsoulas; L. Veng; C. W.
Lindsley; W. Shipe; S. Kuduk; C. Sur; G. Kinney; G. R. Seabrook; W.
J. Ray, Proc. Natl. Acad. Sci. USA 2009, 106, 15950-15955.
[38] S. D. Kuduk; D. C. Beshore, Curr. Top. Med. Chem. 2014, 14,
1738-1754.
[10] P. De Sarno; S. A. Shestopal; T. D. King; A. Zmijewska; L. Song;
R. S. Jope, J. Biol. Chem. 2003, 278, 11086-11093.
[11] C. R. Overk; C. C. Felder; Y. Tu; D. A. Schober; K. R. Bales; J.
Wuu; E. J. Mufson, J. Chem. Neuroanat. 2010, 40, 63-70.
[12] E. P. Lebois; J. P. Schroeder; T. J. Esparza; T. M. Bridges; C. W.
Lindsley; P. J. Conn; D. L. Brody; J. S. Daniels; A. I. Levey, ACS
Chem. Neurosci. 2017, 8, 1177-1187.
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