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

• Novel bis(ammonio)alkane-type derivatives were designed, synthesized and tested.
• In vitro, they behaved as muscarinic agonists and weak cholinesterase inhibitors.
• In vivo, they showed relevant analgesic effects in the acetic acid writhing test.
• A promising antinociceptive profile was particularly displayed by compound 8b.
• The analgesic properties are due to a peripherally mediated muscarinic activation.

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.

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