The molecular conformation of clonidine hydrochloride, an α-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-C_2′= 76 ° and C₁-N₁-C_2′-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 C_2′-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 (N_1′,) 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.