THE MOLECULAR-CONFORMATION OF CLONIDINE HYDROCHLORIDE, AN ALPHA-ADRENERGIC AGONIST

The molecular conformation of the antihypertensive drug clonidine hydrochloride [2-(2,6-dichlorophenylimino)-2-imidazole HCl] has been shown by crystallographic studies to have a nearly perpendicular arrangement of the phenyl and imidazole rings as described by the torsion angles C2-C1-N1-C2′= 76 ° and C1-N1-C2′-N′1 = 0 °. This conformation is not either of those suggested as the minimum energy form by CNDO/2 calculations for the protonated or free-base models. However, it is consistent with a nonplanar model proposed as the active conformer based on QSAR and spectral studies. The bonding about the imidazole carbon is similar to the guanidinium ion and the three C2′-N distances of the planar imidazole ring are nearly equal. The chloride ion forms strong hydrogen bonds with the amine hydrogen (2.3 Å) and the imidazole (N1′,) hydrogen (2.4 Å). Comparison with α-adrenergic agonists shows that this conformation of clonidine fits the proposed pharmacophore model and should compete effectively for the α-adrenergic receptors. © 1980 Plenum Publishing Corporation.