Ogg G D, Neilson D G, Stevenson I H, Lyles G A
J Pharm Pharmacol. 1987 May;39(5):378-83. doi: 10.1111/j.2042-7158.1987.tb03401.x.
The two enantiomers ((R)- and (S)-) of propranolol glycol, a metabolite of propranolol, have been synthesized, and their effects upon the beta-adrenoceptor studied by two methods. The ability of these compounds to antagonize the inotropic actions of isoprenaline was examined on spontaneously beating rat atrial preparations. Also, the effects of these enantiomers upon the binding of [3H]dihydroalprenolol to beta-receptors in rat cardiac ventricular membranes was studied. Experiments with the atria indicated that the (S)-glycol was a reversible competitive antagonist of isoprenaline with a potency approximately one thousand times lower than that of (+/-)-propranolol. In contrast, the (R)-glycol appeared to act as an irreversible antagonist, producing complex dose-response curves. The effects of these compounds to cause displacement of alprenolol binding were consistent with the organ bath data. The interaction of the (S)-glycol with the beta-receptor binding site was reversible (Ki of 27.6 +/- 4.2 microM) but less potent than that of (+/-)-propranolol (Ki of 0.99 +/- 0.07 nM). On the other hand, pretreatment of ventricular membranes with the (R)-glycol, followed by extensive washing techniques, resulted in alprenolol binding which did not regain control values, providing further evidence for an irreversible effect upon the beta-receptor. The possible significance of these pharmacological actions of the two enantiomers is discussed in terms of the in vivo metabolic pathways for propranolol.
普萘洛尔的代谢产物普萘洛尔二醇的两种对映体（(R)-和(S)-）已被合成，并通过两种方法研究了它们对β-肾上腺素受体的作用。在自发搏动的大鼠心房标本上检测了这些化合物拮抗异丙肾上腺素变力作用的能力。此外，还研究了这些对映体对[3H]二氢阿普洛尔与大鼠心室膜β受体结合的影响。心房实验表明，(S)-二醇是异丙肾上腺素的可逆竞争性拮抗剂，其效力比(±)-普萘洛尔低约一千倍。相比之下，(R)-二醇似乎作为不可逆拮抗剂起作用，产生复杂的剂量反应曲线。这些化合物引起阿普洛尔结合位移的作用与器官浴数据一致。(S)-二醇与β受体结合位点的相互作用是可逆的（Ki为27.6±4.2微摩尔），但效力低于(±)-普萘洛尔（Ki为0.99±0.07纳摩尔）。另一方面，用(R)-二醇预处理心室膜，然后采用广泛的洗涤技术，导致阿普洛尔结合不能恢复到对照值，这为其对β受体的不可逆作用提供了进一步证据。根据普萘洛尔的体内代谢途径讨论了这两种对映体这些药理作用的可能意义。
