Moxonidine, a centrally acting antihypertensive agent, is a selective ligand for I1-imidazoline sites.

Both the hypotension and the sedation elicited by centrally acting antihypertensive agents are traditionally attributed to activation of alpha 2 adrenergic receptors. Second-generation centrally acting agents such as moxonidine are less sedating but retain antihypertensive efficacy. A novel receptor which recognizes imidazolines may contribute to their vasodepressor action in the ventrolateral medulla (VLM). We sought to determine whether moxonidine was a selective ligand for these putative I1-imidazoline receptors in different species and tissues. Moxonidine inhibited [3H]clonidine binding to bovine VLM membranes in a heterogeneous manner, showing 40-fold selectivity for one component. Masking studies using selective inhibitors to block either I1-imidazoline or alpha 2 sites established that the population of sites showing high affinity for moxonidine were I1-imidazoline sites. Moxonidine also showed 70-fold selectivity for I1-imidazoline sites labeled by [125I]p-iodoclonidine in the VLM. Moxonidine competitively inhibited [3H]clonidine binding to I1-imidazoline sites at concentrations that failed to inhibit alpha 2 binding. In the rat renal medulla, moxonidine showed almost 700-fold selectivity for I1-imidazoline sites relative to the alpha 2B receptor subtype. The high affinity of moxonidine for I1 sites was confirmed by using membranes prepared from bovine adrenomedullary cells, which lack alpha 2 adrenergic receptors. Among centrally acting antihypertensives, clinical potency correlated with binding affinity at bovine VLM I1-imidazoline sites (r = 0.996, N = 4), but not with alpha 2 adrenergic affinity (r = -0.239, N = 6). The potent action of moxonidine on I1-imidazoline receptors may account for its antihypertensive efficacy.