Carbachol dimers as homobivalent modulators of muscarinic receptors

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• 作者：Rosanna Matucci^a ; ^{rosanna.matucci@unifi.it" class="auth_mail" title="E-mail the corresponding author} ; Marta Nesi^a ; Maria Vittoria Martino^b ; Cristina Bellucci^b ; Dina Manetti^b ; Elisa Ciuti^a ; Angelica Mazzolari^c ; Silvia Dei^b ; Luca Guandalini^b ; Elisabetta Teodori^b ; Giulio Vistoli^c ; Maria Novella Romanelli^b
• 关键词：Carbachol chloride (PubChem CID ; 5831) ; Acetylcholine chloride (PubChem CID ; 6060) ; Hexamethonium chloride (PubChem CID ; 93550) ; Gallamine triethiodide (PubChem CID ; 6172) ; Atropine sulfate (PubChem CID ; 64663)
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：108
• 期：Complete
• 页码：90-101
• 全文大小：1994 K

文摘

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 hM₁, hM₂ and hM₃ 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 hM₁ and hM₂ 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.