Matera Carlo, Flammini Lisa, Quadri Marta, Vivo Valentina, Ballabeni Vigilio, Holzgrabe Ulrike, Mohr Klaus, De Amici Marco, Barocelli Elisabetta, Bertoni Simona, Dallanoce Clelia
Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica "Pietro Pratesi", Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
Eur J Med Chem. 2014 Mar 21;75:222-32. doi: 10.1016/j.ejmech.2014.01.032. Epub 2014 Jan 25.
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.
在本研究中，我们合成了两组双（铵）烷烃类化合物6a - 9a和6b - 9b，并对其进行了体外和体内测试。这些化合物将原正位毒蕈碱激动剂iperoxo纳入了M2选择性变构调节剂W84和萘甲铵的分子片段中。在离体组织制剂上评估了这些杂合衍生物对M1、M2和M3毒蕈碱受体亚型的激动剂效力和效能及其抗胆碱酯酶活性。然后在醋酸扭体试验中对其镇痛作用进行了体内测定，并确定了外周和中枢胆碱能副作用的发生情况。所研究的杂合物表现为强效毒蕈碱激动剂和弱胆碱酯酶抑制剂。对于带有萘甲铵部分的双季铵盐，这些作用比含W84的类似物更明显，并在体内产生了显著的镇痛活性。与萘甲铵相关的化合物8b展现出了有前景的特性，它在测试化合物中具有最强的抗伤害感受作用，同时没有相关的胆碱能副作用。
