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Carbachol dimers with primary carbamate groups as homobivalent modulators of muscarinic receptors.
Eur J Pharmacol. 2020 Jun 10; 883:173183.EJ

Abstract

Although agonists and antagonists of muscarinic receptors have been known for long time, there is renewed interest in compounds (such as allosteric or bitopic ligands, or biased agonists) able to differently and selectively modulate these receptors. As a continuation of our previous research, we designed a new series of dimers of the well-known cholinergic agonist carbachol. The new compounds were tested on the five cloned human muscarinic receptors (hM1-5) expressed in CHO cells by means of equilibrium binding experiments, showing a dependence of the binding affinity on the length and position of the linker connecting the two monomers. Kinetic binding studies revealed that some of the tested compounds were able to slow the rate of NMS dissociation, suggesting allosteric behavior, also supported by docking simulations. Assessment of ERK1/2 phosphorylation on hM1, hM2 and hM3 activation showed that the new compounds are endowed with muscarinic antagonist properties. At hM2 receptors, some compounds were able to stimulate GTPγS binding but not cAMP accumulation, suggesting a biased behavior. Classification, Molecular and cellular pharmacology.

Authors+Show Affiliations

Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, 50139, Firenze, Italy. Electronic address: rosanna.matucci@unifi.it.Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, 50139, Firenze, Italy.Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.Department of Pharmacology & Toxicology, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Str. 3, 53121, Bonn, Germany.Department of Natural Sciences, H-BRS University of Applied Sciences, von-Liebig-Str. 20, 53359, Rheinbach, Germany.Department of Pharmacology & Toxicology, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Str. 3, 53121, Bonn, Germany.Department of Pharmacology & Toxicology, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Str. 3, 53121, Bonn, Germany.Department of Pharmacology & Toxicology, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Str. 3, 53121, Bonn, Germany.Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133, Milano, Italy.Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133, Milano, Italy.Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32534072

Citation

Matucci, Rosanna, et al. "Carbachol Dimers With Primary Carbamate Groups as Homobivalent Modulators of Muscarinic Receptors." European Journal of Pharmacology, vol. 883, 2020, p. 173183.
Matucci R, Bellucci C, Martino MV, et al. Carbachol dimers with primary carbamate groups as homobivalent modulators of muscarinic receptors. Eur J Pharmacol. 2020;883:173183.
Matucci, R., Bellucci, C., Martino, M. V., Nesi, M., Manetti, D., Welzel, J., Bartz, U., Holze, J., Tränkle, C., Mohr, K., Mazzolari, A., Vistoli, G., Dei, S., Teodori, E., & Romanelli, M. N. (2020). Carbachol dimers with primary carbamate groups as homobivalent modulators of muscarinic receptors. European Journal of Pharmacology, 883, 173183. https://doi.org/10.1016/j.ejphar.2020.173183
Matucci R, et al. Carbachol Dimers With Primary Carbamate Groups as Homobivalent Modulators of Muscarinic Receptors. Eur J Pharmacol. 2020 Jun 10;883:173183. PubMed PMID: 32534072.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carbachol dimers with primary carbamate groups as homobivalent modulators of muscarinic receptors. AU - Matucci,Rosanna, AU - Bellucci,Cristina, AU - Martino,Maria Vittoria, AU - Nesi,Marta, AU - Manetti,Dina, AU - Welzel,Jessica, AU - Bartz,Ulrike, AU - Holze,Janine, AU - Tränkle,Christian, AU - Mohr,Klaus, AU - Mazzolari,Angelica, AU - Vistoli,Giulio, AU - Dei,Silvia, AU - Teodori,Elisabetta, AU - Romanelli,Maria Novella, Y1 - 2020/06/10/ PY - 2019/10/09/received PY - 2020/03/23/revised PY - 2020/05/08/accepted PY - 2020/6/14/pubmed PY - 2020/6/14/medline PY - 2020/6/14/entrez KW - Acethylcholine chloride KW - Allosteric modulation KW - Atropine sulphate KW - Carbachol chloride KW - Carbachol dimers KW - Gallamine triethiodide KW - Hexamethonium chloride KW - McN-A-343 chloride KW - Muscarinic acetylcholine receptor (mAChR) KW - PubChem CID: 5831 KW - PubChem CID: 5926 KW - PubChem CID: 6060 KW - PubChem CID: 6172 KW - PubChem CID: 64663 KW - PubChem CID: 93550 SP - 173183 EP - 173183 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 883 N2 - Although agonists and antagonists of muscarinic receptors have been known for long time, there is renewed interest in compounds (such as allosteric or bitopic ligands, or biased agonists) able to differently and selectively modulate these receptors. As a continuation of our previous research, we designed a new series of dimers of the well-known cholinergic agonist carbachol. The new compounds were tested on the five cloned human muscarinic receptors (hM1-5) expressed in CHO cells by means of equilibrium binding experiments, showing a dependence of the binding affinity on the length and position of the linker connecting the two monomers. Kinetic binding studies revealed that some of the tested compounds were able to slow the rate of NMS dissociation, suggesting allosteric behavior, also supported by docking simulations. Assessment of ERK1/2 phosphorylation on hM1, hM2 and hM3 activation showed that the new compounds are endowed with muscarinic antagonist properties. At hM2 receptors, some compounds were able to stimulate GTPγS binding but not cAMP accumulation, suggesting a biased behavior. Classification, Molecular and cellular pharmacology. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/32534072/Carbachol_dimers_with_primary_carbamate_groups_as_homobivalent_modulators_of_muscarinic_receptors L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(20)30275-2 DB - PRIME DP - Unbound Medicine ER -
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