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  2. Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity

Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity

  • Eur J Med Chem. 2014 Mar 21:75:222-32. doi: 10.1016/j.ejmech.2014.01.032.
Carlo Matera 1 Lisa Flammini 2 Marta Quadri 1 Valentina Vivo 2 Vigilio Ballabeni 2 Ulrike Holzgrabe 3 Klaus Mohr 4 Marco De Amici 1 Elisabetta Barocelli 2 Simona Bertoni 2 Clelia Dallanoce 5
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
  • 2 Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
  • 3 Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • 4 Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany.
  • 5 Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy. Electronic address: clelia.dallanoce@unimi.it.
Abstract

In this study, we synthesized and tested in vitro and in vivo two groups of bis(ammonio)alkane-type compounds, 6a-9a and 6b-9b, which incorporate the orthosteric muscarinic agonist iperoxo into a molecular fragment of the M2-selective allosteric modulators W84 and naphmethonium. The agonist potency and efficacy of these hybrid derivatives at M1, M2 and M3 muscarinic receptor subtypes and their anticholinesterase activity were evaluated on isolated tissue preparations. Their analgesic action was then assayed in vivo in the acetic acid writhing test and the occurrence of peripheral and central cholinergic side effects was also determined. The investigated hybrids behaved as potent muscarinic agonists and weak cholinesterase inhibitors. These effects were more pronounced for bisquaternary salts bearing the naphmethonium moiety than for the W84-containing analogs, and resulted in a significant analgesic activity in vivo. A promising profile was displayed by the naphmethonium-related compound 8b, which combined the most potent antinociception among the test compounds with the absence of relevant cholinergic side effects.

Keywords

Alkylbisammonio quaternary salts; Analgesic activity; In vitro pharmacology; In vivo pharmacology; Muscarinic agonists; Muscarinic receptor subtypes.

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