Arnett C D, Wright J, Zenker N
J Med Chem. 1978 Jan;21(1):72-8. doi: 10.1021/jm00199a013.
The concept of bioisosterism between benzimidazole and catechol was applied to the design and synthesis of benzimidazole analogues of norepinephrine, (R,S)-1-[5(6)-benzimidazolyl]-2-aminoethanol (2), and of isoproterenol, (R,S)-1-[5(6)-benzimidazolyl]-2-isopropylaminoethanol (4). Compound 2 was shown to be a partial bioisostere of norepinephrine, with direct agonist activity at the alpha-adrenergic receptor. The ED50 for 2 in contracting the guinea pig isolated aortic strip was determined to be 8.0 x 10(-6) M. Compound 4 was shown to be a partial bioisostere of isoproterenol, with direct activity as a beta-adrenergic agonist. The ED50 values for positive chronotropic and inotropic effects of 4 on the isolated guinea pig atrial preparation were determined to be 6.2 x 10(-6) and 3.8 x 10(-6) M, respectively. The ED50 for 4 on the isolated guinea pig tracheal preparation was determined to be 1.6 x 10(-6) M. These results indicate that 4 shows greater selectively for the beta-2 adrenergic receptor than does isoproterenol. The chemical stability of benzimidazole, compared with that of catechol, suggests that benzimidazole bioisosteres of catecholamines may be of value as adrenergic drugs.
苯并咪唑与儿茶酚之间的生物电子等排体概念被应用于去甲肾上腺素的苯并咪唑类似物（R,S）-1-[5(6)-苯并咪唑基]-2-氨基乙醇（2）以及异丙肾上腺素的苯并咪唑类似物（R,S）-1-[5(6)-苯并咪唑基]-2-异丙氨基乙醇（4）的设计与合成中。化合物2被证明是去甲肾上腺素的部分生物电子等排体，对α-肾上腺素能受体具有直接激动活性。在收缩豚鼠离体主动脉条实验中，化合物2的半数有效浓度（ED50）被测定为8.0×10⁻⁶ M。化合物4被证明是异丙肾上腺素的部分生物电子等排体，作为β-肾上腺素能激动剂具有直接活性。在离体豚鼠心房标本实验中，化合物4对正性变时和变力作用的ED50值分别被测定为6.2×10⁻⁶ M和3.8×10⁻⁶ M。在离体豚鼠气管标本实验中，化合物4的ED50被测定为1.6×10⁻⁶ M。这些结果表明，化合物4对β-2肾上腺素能受体的选择性高于异丙肾上腺素。与儿茶酚相比，苯并咪唑的化学稳定性表明，儿茶酚胺的苯并咪唑生物电子等排体作为肾上腺素能药物可能具有价值。
