Imidazoline Antihypertensive Drugs: Selective I1-Imidazoline Receptors Activation

Abstract

Involvement of imidazoline receptors (IR) in the regulation of vasomotor tone as well as in the mechanism of action of some centrally acting antihypertensives has received tremendous attention. To date, pharmacological studies have allowed the characterization of three main imidazoline receptor classes, the I1-imidazoline receptor which is involved in central inhibition of sympathetic tone to lower blood pressure, the I2-imidazoline receptor which is an allosteric binding site of monoamine oxidase B (MAO-B), and the I3-imidazoline receptor which regulates insulin secretion from pancreatic beta-cells. All three imidazoline receptors represent important targets for cardiovascular research. The hypotensive effect of clonidine-like centrally acting antihypertensives was attributed both to a2-adrenergic receptors and nonadrenergic I1-imidazoline receptors, whereas their sedative action involves activation of only a2-adrenergic receptors located in the locus coeruleus. Since more selective I1-imidazoline receptors ligands reduced incidence of typical side effects of other centrally acting antihypertensives, there is significant interest in developing new agents with higher selectivity and affinity for I1-imidazoline receptors. The selective imidazoline receptors agents are also more effective in regulation of body fat, neuroprotection, inflammation, cell proliferation, epilepsy, depression, stress, cell adhesion, and pain. New agonists and antagonists with high selectivity for imidazoline receptor subtypes have been recently developed. In the present review we provide a brief update to the field of imidazoline research, highlighting some of the chemical diversity and progress made in the theoretical studies of imidazoline receptor ligands.