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Carbachol dimers as homobivalent modulators of muscarinic receptors.

Authors :
Matucci, Rosanna
Nesi, Marta
Martino, Maria Vittoria
Bellucci, Cristina
Manetti, Dina
Ciuti, Elisa
Mazzolari, Angelica
Dei, Silvia
Guandalini, Luca
Teodori, Elisabetta
Vistoli, Giulio
Romanelli, Maria Novella
Source :
Biochemical Pharmacology. May2016, Vol. 108, p90-101. 12p.
Publication Year :
2016

Abstract

A series of homodimers of the well-known cholinergic agonist carbachol have been synthesized, showing the two agonist units symmetrically connected through a methylene chain of variable length. The new compounds have been tested on the five cloned muscarinic receptors (hM 1–5 ) expressed in CHO cells by means of equilibrium binding studies, showing an increase in affinity by rising the number of methylene units up to 7 and 9. Functional experiments on guinea-pig ileum and assessment of ERK1/2 phosphorylation on hM 1 , hM 2 and hM 3 on CHO cells have shown that the new compounds are endowed with muscarinic antagonistic properties. Kinetic binding studies have revealed that some of the tested compounds are able to slow the rate of dissociation of NMS, suggesting a bitopic behavior. Docking simulations, performed on the hM 1 and hM 2 receptors, give a sound rationalization of the experimental data revealing how these compounds are able to interact with both orthosteric and allosteric binding sites depending on the length of their connecting chain. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00062952
Volume :
108
Database :
Academic Search Index
Journal :
Biochemical Pharmacology
Publication Type :
Academic Journal
Accession number :
114628647
Full Text :
https://doi.org/10.1016/j.bcp.2016.03.012