New 2-Aminothiazoline derivatives lower blood pressure of spontaneously hypertensive rats (SHR) via I1-imidazoline and alpha-2 adrenergic receptors activation (original) (raw)
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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.
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.
BioMed Research International, 2014
It has been indicated that activation of peripheral imidazoline I2-receptor (I-2R) may reduce the blood pressure in spontaneously hypertensive rats (SHRs). Also, guanidinium derivatives show the ability to activate imidazoline receptors. Thus, it is of special interest to characterize the I-2R using guanidinium derivatives in blood vessels for development of antihypertensive agent(s). Six guanidinium derivatives including agmatine, amiloride, aminoguanidine, allantoin, canavanine, and metformin were applied in this study. Western blot analysis was used for detecting the expression of imidazoline receptor in tissues of Wistar rats. The isometric tension of aortic rings isolated from male rats was also estimated. The expression of imidazoline receptor on rat aorta was identified. However, guanidinium derivatives for detection of aortic relaxation were not observed except agmatine and amiloride which induced a marked relaxation in isolated aortic rings precontracted with phenylephrine ...
Journal of Pharmacy and Pharmacology, 1997
The antihypertensive activity of eighteen oxazolo[3,2-a]pyridine, fhiazolo[3,2-a]pyridine and pyrido[2,1-b]oxazine derivatives has been evaluated in conscious spontaneously hypertensive rats (SHRs), and compared with that of nifedipine, used as reference. At a dose of 50 mg kg−1 (i.p.) eleven compounds resulted in a significant reduction in mean arterial blood pressure; four of the eleven were particularly effective, resulting in significant hypotension more than 6 h after administration and an effect that was still apparent after 24 h. The hypotension induced by nifedipine gradually decreased, disappearing 6–8 h after administration. The long-lasting activity shown by these compounds is, in general, not accompanied by reflex tachycardia. Intraperitoneal administration of two oxazolo[3,2-a]pyridine derivatives and two pyrido[2,1-b]oxazine derivatives resulted in potent and long-lasting antihypertensive action in SHRs. Further studies on the mechanism of action of these derivatives m...
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...
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.
In the present study, fourteen derivatives comprising of 5-benzylidene-2-(phenylimino)-thiazolidin-4-one moiety were synthesized. The structures of synthesized compounds were established by elemental analysis, IR, 1 H NMR, 13 C NMR and mass spectral data and tested for electrocardiographic, antiarrhythmic and antihypertensive activities. Compound 11 was found to be most potent in this series. The pharmacological results suggested that, the antiarrhythmic effects of these compounds were related to their Ca þþ ion channel antagonistic properties, which are believed to be due to the presence of 5-benzilidine-2-(phenylimino)-thiazolidin-4-one moiety. The antihypertensive effect of b-blocker side chain is enhanced by the presence of less bulky aliphatic and heterocyclic tertiary amines.
Journal of medicinal chemistry, 2015
New 2-aryliminopyrrolidines (1-18) were synthesized and tested for their binding properties on I1 imidazoline receptors vs α2-adrenergic receptors and their blood pressure effects after both systemic and intracerebral administrations. The purposes of this study were: (i) to analyze structure-activity and affinity relationships on I1 imdazoline receptors and (ii) to propose some leader compounds for the development of new sympatho-inhibitory drugs with potential applications in hypertension and/or metabolic syndrome, i.e., a cluster of cardiovascular (hypertension) and metabolic disorders. Our study highlights decisive arguments of SAR concerning both the affinity for I1Rs and the hypotensive activity of 2-aryliminopyrrolidines. Binding assays showed high affinity and selectivity of some compounds for I1 imidazoline receptors over α2-adreergic receptors. Compound 13 (laboratory reference LNP599; Ki = 3.2 nM on I1imidazoline receptors) is the prototype for the development of new centr...
Bioorganic & Medicinal Chemistry, 2009
The synthesis and pharmacological profile of a series of hybrid compounds bearing the dihydropyrimidine moiety and substituted phenylthioureas joined via typical b-blocker aryloxypropanolamine group are described. Seven out of 10 new compounds tested proved to be endowed with negative inotropic and chronotropic effect as compared to Adrenaline on isolated perfused frog heart. Also ECG studies that were carried out on normotensive male rats showed that the most of the compounds exhibited significant reduction in Rmax value in the first 30 min although maintaining little change in heart rate, with hypotensive effect lasting for 1 h. We concluded that the most of the synthesized novel compounds exhibited hypotensive as well as antihypertensive effects which could be attributed to blockade of Ca 2? entry and b-adrenoreceptor blocking activities due to introduction of aryloxypropanolamine linked to N-1 substituted dihydropyrimidine moiety. Brady cardiac effects of compounds 5a-5d, 6c-6e resulting from Ca 2? entry and b-adrenoreceptor blocking attenuate the sympathetic activation-associated reflex tachycardia in the heart. We selected compound 5c as a promising lead for further detailed pharmacological and preclinical evaluation studies.