Synthesis and adrenergic activity of benzimidazole bioisosteres of norepinephrine and isoproterenol

Abstract

The concept of bioisosterism between benzimidazole and catechol was applied to the design and synthesis of benzimidazole analogs 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 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 .times. 10-6 M. Compound 4 was 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 .times. 10-6 and 3.8 .times. 10-6 M, respectively. The ED50 for 4 on the isolated guinea-pig tracheal preparation was determined to be 1.6 .times. 10-6 M. Analog 4 showed greater selectivity for the .beta.-2 adrenergic receptor than did isoproterenol. The chemical stability of benzimidazole, compared with that of catechol, suggested that benzimidazole bioisosteres of catecholamines may be of value as adrenergic drugs.