Conway P G, Tejani-Butt S, Brunswick D J
J Pharmacol Exp Ther. 1987 Jun;241(3):755-62.
There is interest in knowing whether beta adrenergic antagonists or agonists, when administered systemically, can enter the brain to interact with central beta adrenergic receptors. To study this, the reduction in the radioactive content in the brain of rats after administration of (-)-[125I]iodopindolol (IPIN) by systemically administered beta agonists or antagonists was measured. Previous studies show that after the i.v. administration of IPIN the binding in vivo to various areas of the central nervous system has the characteristics expected of binding to beta adrenergic receptors. Of the antagonists tested, pindolol and butylpindolol showed potent interactions with beta receptors in both cortex and cerebellum whereas atenolol and practolol did not interact at doses up to 30 mg/kg. CGP-12177 showed moderate potency in inhibiting IPIN binding in vivo. We have shown previously that propranolol and alprenolol inhibit IPIN binding with high potency in cortex and cerebellum. At high doses, butoxamine, a beta-2 antagonist, reduced the binding of IPIN in the cerebellum but not in the cortex. Of the agonists tested, clenbuterol and prenalterol caused a significant dose-dependent reduction of the binding of IPIN, with clenbuterol being more potent. Isoproterenol, salbutamol, salmefamol and dobutamine had no effect. With the exception of CGP-12177, the affinity of the drugs for central beta adrenergic receptors measured in vitro was correlated significantly with their ability to inhibit IPIN binding in vivo whereas their degree of lipophilicity was not correlated significantly with potency in vivo. The inhibition of IPIN binding in vivo from brain areas can be used to evaluate whether drugs penetrate into brain and interact with central beta adrenergic receptors.
人们想知道β肾上腺素能拮抗剂或激动剂经全身给药后是否能进入大脑与中枢β肾上腺素能受体相互作用。为了研究这一点，测量了全身给予β激动剂或拮抗剂后大鼠脑中（-）-[¹²⁵I]碘吲哚洛尔（IPIN）给药后放射性含量的降低情况。先前的研究表明，静脉注射IPIN后，其在体内与中枢神经系统各个区域的结合具有与β肾上腺素能受体结合所预期的特征。在所测试的拮抗剂中，吲哚洛尔和丁吲哚洛尔在皮质和小脑中均显示出与β受体的强效相互作用，而阿替洛尔和美托洛尔在高达30mg/kg的剂量下没有相互作用。CGP-12177在体内抑制IPIN结合方面显示出中等效力。我们之前已经表明，普萘洛尔和阿普洛尔在皮质和小脑中高效抑制IPIN结合。高剂量时，β2拮抗剂布托沙明降低了IPIN在小脑中的结合，但在皮质中没有。在所测试的激动剂中，克伦特罗和丙卡特罗导致IPIN结合的显著剂量依赖性降低，克伦特罗更有效。异丙肾上腺素、沙丁胺醇、沙美特罗和多巴酚丁胺没有作用。除CGP-12177外，体外测量的药物对中枢β肾上腺素能受体的亲和力与其在体内抑制IPIN结合的能力显著相关，而它们的亲脂性程度与体内效力没有显著相关性。脑区中IPIN结合的体内抑制可用于评估药物是否穿透进入大脑并与中枢β肾上腺素能受体相互作用。
