A historical perspective: development of clonidine

At the beginning of the 1960s Boehringer Ingelheim planned to synthesize a peripherally active adrenergic compound for nasal decongestion as simple nose drops. Imidazoline-derivatives with decongestive properties are substituted amidines in which the amidine function is incorporated into an imidazoline structure. However, at that time a replacement of the –CH2– bridge by an –NH– group had not been achieved chemically in compounds substituted at both the 2- and 6-positions of the phenyl ring. The problem was solved by introducing chlorine atoms as substituents. Although the resulting drug indeed had a remarkably high vasoconstructive and decongestive effect at low concentrations, it turned out that other effect were more significant. After administration of the drug to a secretary she fell asleep for 24 h, developed low blood pressure, marked bradycardia, and dryness of the mouth. Clonidine was subsequently developed for its blood-lowering effect and introduced into the clinical routine in 1966. Besides its therapeutic value, clonidine has proved to be an essential pharmacological tool and has provided valuable insight into the importance of central α2-adrenoceptors.