Dambrova Maija, Chlopicki Stefan, Liepinsh Edgars, Kirjanova Olga, Gorshkova Olga, Kozlovski Valery I, Uhlen Staffan, Liepina Inta, Petrovska Ramona, Kalvinsh Ivars
Department of Medicinal Chemistry, Latvian Institute of Organic Synthesis, Aizkraukles 21, LV1006 Riga, Latvia.
Naunyn Schmiedebergs Arch Pharmacol. 2004 May;369(5):533-9. doi: 10.1007/s00210-004-0925-6. Epub 2004 Apr 2.
Gamma-butyrobetaine (GBB) is known mostly as a bio-precursor of carnitine, a key molecule in the regulation of myocardial energy metabolism. The metabolites of carnitine and GBB were investigated for acetylcholine-like activity decades ago. The present study shows that the methylester of GBB (GBB-ME) exerts its biological activity by binding to muscarinic acetylcholine receptors. GBB-ME dose-dependently decreased the blood pressure in anaesthetised rats and also produced endothelium-dependent vasodilation in the isolated guinea-pig heart. The biological effects of GBB-ME were inhibited partially by the NOS inhibitor N(omega)-nitro-L-arginine methylester (L-NAME) and abolished by the acetylcholine receptor antagonist atropine, thus supporting the hypothesis that GBB-ME acts as muscarinic agonist. Moreover, we have shown here for the first time that GBB-ME binds directly to transfected human muscarinic (m) acetylcholine receptors, the potency order being m2>m5> or =m4> or =m1>m3. GBB itself showed neither biological activity nor significant affinity for the m1-5 receptors. We conclude that GBB-ME, but not the parent GBB, possesses acetylcholine-like activity in vivo and in vitro.
γ-丁基甜菜碱（GBB）主要作为肉碱的生物前体为人所知，肉碱是调节心肌能量代谢的关键分子。几十年前就对肉碱和GBB的代谢产物进行了乙酰胆碱样活性的研究。本研究表明，GBB的甲酯（GBB-ME）通过与毒蕈碱型乙酰胆碱受体结合发挥其生物活性。GBB-ME剂量依赖性地降低麻醉大鼠的血压，并在离体豚鼠心脏中产生内皮依赖性血管舒张。GBB-ME的生物学效应被一氧化氮合酶抑制剂N（ω）-硝基-L-精氨酸甲酯（L-NAME）部分抑制，并被乙酰胆碱受体拮抗剂阿托品消除，从而支持GBB-ME作为毒蕈碱激动剂的假说。此外，我们首次在此表明GBB-ME直接与转染的人毒蕈碱（m）乙酰胆碱受体结合，效力顺序为m2>m5≥m4≥m1>m3。GBB本身对m1-5受体既无生物活性也无明显亲和力。我们得出结论，GBB-ME而非母体GBB在体内和体外均具有乙酰胆碱样活性。
