Central and peripheral alpha adrenergic activity of imidazoline derivatives

Intravenous injection of a number of imidazoline derivatives into rats induced an increase in blood pressure due to peripheral alpha adrenergic receptor stimulation. Some of these compounds, however, caused a secondary, long lasting decrease which was caused by central nervous system alpha adrenergic receptor stimulation. This central hypotensive action was only observed in the case of 2-amino-imidazolines such as clonidine, tramazoline and St 600, a clonidine analogue. Imidazolines lacking the nitrogen between the imidazoline and the benzene or naphtalene group such as oxymetazoline, xylometazoline and naphazoline were found to exert no central hypotensive action.Within the series of 2-amino-imidazolines lipid solubility turned out to be a major factor in the potency of a drug's central hypotensive action.Oxymetazoline — peripherally a very potent alpha adrenergic receptor stimulating agent — did not even cause hypotension when injected into the anterior hypothalamus, a brain structure where alpha adrenergic receptors mediating depressor effects have been localized. These data show that the hypothalamic alpha adrenergic receptors differ from peripheral alpha receptors and that only imidazolines with 2-amino substitution show affinity for these central hypotensive alpha adrenergic receptors.