Characterization of Imidazoline Receptors in Blood Vessels for the Development of Antihypertensive Agents (original) (raw)
Related papers
Annals of the New York Academy of Sciences, 1995
It has been suggested that baroreflex control of blood pressure by the autonomic nervous system is limited to the short term, while the kidney plays a major role in determining the long-term level of blood pressure.' However, much evidence now supports the view that the sympathetic nervous system is activated in the early phases of hypertension and that this may be a contributory factor to the disease.* The increase in sympathetic drive is not generalized but is confined to renal and cardiac beds.
Imidazoline antihypertensive drugs: a critical review on their mechanism of action
Pharmacology & Therapeutics, 2002
It was long thought that the prototypical centrally acting antihypertensive drug clonidine lowers sympathetic tone by activating a 2-adrenoceptors in the brain stem. Supported by the development of two new centrally acting drugs, rilmenidine and moxonidine, the imidazoline hypothesis evolved recently. It assumes the existence of a new group of receptors, the imidazoline receptors, and attributes the sympathoinhibition to activation of I 1 imidazoline receptors in the medulla oblongata. This review analyzes the mechanism of action of clonidine-like drugs, with special attention given to the imidazoline hypothesis. Two conclusions are drawn. The first is that the arguments against the imidazoline hypothesis outweigh the observations that support it and that the sympathoinhibitory effects of clonidine-like drugs are best explained by activation of a 2-adrenoceptors. The second conclusion is that this class of drugs lowers sympathetic tone not only by a primary action in cardiovascular regulatory centres in the medulla oblongata. Peripheral presynaptic inhibition of transmitter release from postganglionic sympathetic neurons contributes to the overall sympathoinhibition.
Imidazoline Antihypertensive Drugs: Selective I1-Imidazoline Receptors Activation
Cardiovascular Therapeutics, 2012
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 I 1 -imidazoline receptor which is involved in central inhibition of sympathetic tone to lower blood pressure, the I 2 -imidazoline receptor which is an allosteric binding site of monoamine oxidase B (MAO-B), and the I 3 -imidazoline receptor which regulates insulin secretion from pancreatic β-cells. All three imidazoline receptors represent important targets for cardiovascular research. The hypotensive effect of clonidine-like centrally acting antihypertensives was attributed both to α 2 -adrenergic receptors and nonadrenergic I 1 -imidazoline receptors, whereas their sedative action involves activation of only α 2 -adrenergic receptors located in the locus coeruleus. Since more selective I 1 -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 I 1 -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.
Structureactivity studies of new imidazolines on adrenoceptors of rat aorta and human platelets
Naunyn-schmiedebergs Archives of Pharmacology, 1991
Potencies of new aromatic substituted fluoro or iodo analogues of catecholimidazolines on functional responses in rat aorta (α1) and platelets (α2) were quantified. (1) When compared either on the basis of EC50 or the dissociation constant (KA), 5-fluorocatecholimidazoline was as potent as the reference α1-adrenoceptor agonist, phenylephrine in the vascular tissue. The maximum contraction of aorta produced by the fluoro analogue was, however, 17% higher than that of phenylephrine. The time required for 1/2 relaxation of the tissue after 5-fluoro hydroxy imidazoline was at least twice as long as that of the phenylephrine. The catechol moiety as well as fluorine substitution at the critical 5-position of the aromatic ring is essential for higher α1 adrenoceptor-mediated potency. (2) As compared to the fluoro analogues, the adrenoceptor-mediated potencies of iodo-analogues were relatively weak on vascular tissue. Naphazoline and its analogues were partial agonists on vascular tissue with dissociation constants which ranged from 110 to 2600 nmol/l. (3) Imidazole analogues were generally less potent agonist than the imidazolines by one order of magnitude. (4) The vascular effects of all agonists were competitively blocked by prazosin with KB values which ranged from 0.04 to 0.48 nmol/l. Since the variation in KB values were within normal limits, the action of new imidazolines on rat aorta appears to be mediated mainly by the activation of the α1-adrenoceptor. Prazosin 10 nmol/l abolished the vascular response of some partial agonists. This indicates a slightly different mode of interaction of agonists with the transduction process. (5) Carbon 4-substituted imidazolines produced little or no α1 adrenoceptor-mediated intrinsic activity, but competitive receptor blocking potency was comparable to that of phentolamine. (6) Medetomidine was a partial agonist on the rat aorta with a KA of 260 nmol/l. When investigated as a blocker, the KB of medetomidine against phenylephrine was approximately 5600 nmol/l. The variation in the latter value was high. (7) In acetylsalicylic acid-treated human platelets, the α2-adrenoceptor-mediated aggregatory effect of all fluoro analogues was weak. lodo or naphazoline analogues did not initiate platelet aggregation but blocked the aggregation induced by epinephrine. The affinity of naphazoline for the α2-adrenoceptor was 1100 nmol/l. The IC50 of medetomidine for platelet anti-aggregatory effect was 3300 nmol/l, which compares favorably with other imidazoline type of blockes of platelet aggregation. (8) Sympathomimetic vasoconstrictor actions and platelet aggregation effects of these compounds can be dissociated. Some vasoconstrictors were antiaggregatory. The structure-activity relationships of the two receptor systems, namely rat aorta (α1) and platelets (α2), are discussed.
ACS Medicinal Chemistry Letters, 2015
Pharmacological studies have suggested that I 1 -imidazoline receptors are involved in the regulation of cardiovascular function and that selective I 1agonists, devoid of the side effects associated with the common hypotensive α 2adrenoreceptor agonists, might be considered as a second generation of centrally acting antihypertensives. Therefore, in the present study, inspired by the antihypertensive behavior of our selective I 1 -agonist 4, we designed, prepared, and studied the novel analogues 5−9. A selective I 1 -profile, associated with significant hemodinamic effects, was displayed by 5, 8, and 9. Interestingly, the highest potency and longest lasting activity displayed by 8 (carbomethyline) suggested that van der Waals interactions, promoted by the ortho methyl decoration of its aromatic moiety, are particularly advantageous. In addition, in analogy to what was noted for (S)-(+)-4, the observation that only (S)-(+)-8 displayed significant hemodynamic effects unequivocally confirmed the stereospecific nature of the I 1 proteins.
International Journal of Advances in Medicine, 2019
Hypertension, often referred to as ‘The silent killer’, is christened so, as it is seldom preceded by any warning signs or symptoms. With the new ACC/AHA guidelines lowering the Blood Pressure (BP) threshold values, it has resulted in a 140% relative increase in the hypertension prevalence in India, which is 3 times higher than that of in United States. Imidazoline receptor agonists control BP effectively with minimal adverse effects of sedation and mental depression that are usually associated with centrally acting antihypertensives. While having a low affinity to the α2-adrenergic receptors, these new generation centrally acting antihypertensive agents are highly selective for imidazoline receptor. Moxonidine, a second-generation centrally acting antihypertensive drug having selective agonist activity on imidazoline I1 receptors and minor activity on imidazoline α2 adrenoceptors, reduces the activity of Sympathetic Nervous System (SNS) by activating I1 imidazoline receptors in Ros...
Central Imidazoline Receptors and Centrally Acting Anti-Hypertensive Agents
Clinical and Experimental Hypertension, 1997
We have examined the location and contribution of imidazoline receptors (IR) in mediating the hypotensive and sympatholytic actions of first and second generation anti-hypertensive agents in rabbits. We found that the hypotension produced by rilmenidine and moxonidine given intravenously (IV) or into the fourth ventricle (4V) was preferentially reversed by the IR antagonists idazoxan and efaroxan (compared to a selective R-adrenoceptor antagonist 2-methoxy-idazoxan), suggesting that IR are important in the sympatho-inhibition produced by these agents. Clonidine was not 591 Copyright 0 1997 by Marcel Dekker, Inc. Clin Exp Hypertens Downloaded from informahealthcare.com by Monash University on 02/14/13 For personal use only.
… drugs and therapy, 1994
Sympathoadrenal inhibition by a direct action within the central nervous system is an advantageous route to blood pressure control. Stimulation of brain oLz-adrenergic receptors is one mechanism for sympathoadrenal suppression, but comes at the cost of nonspecific depression of CNS function, including sedation and decreased salivary flow. Evidence is accumulating for a second pathway for pharmacological control of sympathoadrenal outflow, mediated by a novel receptor specific for imidazolines. First-generation central antihypertensive agents, which are imidazolines such as clonidine, act primarily to stimulate these II-imidazoline receptors in the rostral ventrolateral medulla oblongata (RVLM) to lower blood pressure, but have sufficient agonism at a2-adrenergic receptors to produce side effects. Secondgeneration centrally acting antihypertensive agents, such as moxonidine and rilmenidine, are selective for Ix relative to az receptors. The reduced a z potency of these agents correlates with reduced severity of side effects. In this study we further established the selectivity of moxonidine for 11imidazoline sites by characterizing the direct interaction of [alt]moxonidine with these receptors in the RVLM and in adrenomedullary chromaffin cells.