Synthesis and adrenergic activity of benzimidazole bioisosteres of norepinephrine and isoproterenol.
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.
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013566:Sympathomimetics / Q000138:chemical synthesis*
D001562:Benzimidazoles; D013566:Sympathomimetics; D007545:Isoproterenol; D009638:Norepinephrine