Imidazoline Derivatives Research Articles

Evidence for nonadrenoceptor responses to imidazoline derivatives in the porcine isolated rectal artery.

High concentrations of phentolamine, efaroxan, and idazoxan were found to produce nonadrenoceptor contractions of the porcine isolated rectal artery previously exposed to U46619 and forskolin. These responses were insensitive to the putative imidazoline I(3) receptor antagonist KU-14R, unlike those previously reported in this preparation for oxymetazoline. The pharmacologic nature of this response and the obligate requirement for preconstriction suggests that these imidazoline derivatives modulate ion channel function through a novel nonadrenergic site.

Acute exposure to imidazoline derivatives in children

Acute exposure to imidazoline derivatives in children

Exposição aguda a derivados imidazolínicos em crianças

To study acute exposure to imidazoline derivatives in 72 children younger than 15 years of age, followed-up from January 1994 to December 1999. This is a retrospective study of 72 patients with age between 2 months and 13 years (median 2 years; 25-75% = 1 to 3 years old) exposed to naphazoline (N = 48), fenoxazoline (N = 18), oxymetazoline (N = 5) and tetrahydrozoline (N = 1), through oral (N = 46), nasal (N = 24) or unknown (N = 2) routes. Fifty-seven children developed clinical manifestations such as somnolence (N = 34/57), sweating (N = 20/57), pallor (N = 17/57), hypothermia (N = 16/57), bradycardia (N = 13/57), cool extremities (N = 9/57), restlessness (N = 7/57), tachycardia (N = 6/57), vomiting (N = 5/57), irregular respiratory pattern and apnea (N = 5/57), miosis/mydriasis (N = 4/57). Naphazoline was the active ingredient most frequently involved (N = 47), followed by fenoxazoline (N = 5) and oxymetazoline (N = 4). The onset of clinical manifestations was rapid, beginning within 2 hours after exposure in 32/57 children. Only supportive measures were employed, with one child requiring mechanical ventilation after accidental naphazoline ingestion. In most of the children resolution of symptoms occurred within 24 hours (N = 39/57). No deaths were observed. Patients exposed to naphazoline (N = 47/48) presented a higher frequency of clinical signs of poisoning in comparison with those exposed to fenoxazoline (N = 5/18) (p < 0.001). There were no significant differences in the frequency of patients who presented clinical manifestations considering the route of exposure [oral (N = 34/46), nasal (N = 21/24); p = 0.31]. Most children (especially those younger than 3 years) exposed to imidazoline derivatives (especially naphazoline) presented early signs of poisoning regardless of the exposure route (nasal or oral). The main signs observed were nervous system, cardiovascular and respiratory depression. Most children showed complete resolution of the symptoms within 24 hours.

Dissimilar pharmacological responses by a new series of imidazoline derivatives at precoupled and ligand-activated alpha 2A-adrenoceptor states: evidence for effector pathway-dependent differential antagonism.

Whereas agonist-directed differential signaling at a single receptor subtype has become an accepted pharmacological concept, distinct behaviors by ligands that are assumed to be antagonists is less documented. The intrinsic activity and capacity of antagonism for a new series of imidazoline-derived adrenergic ligands analogous to dexefaroxan were investigated by measuring two distinct signaling pathways at the recombinant human alpha 2A-adrenoceptor (alpha 2A AR): 1) pertussis toxin-resistant guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTP gamma S) binding responses mediated by either a recombinant G alpha oCys351Ile or G alpha i2Cys352Ile protein in CHO-K1 cells, and 2) inhibition of cAMP formation in a stably transfected C6-glial cell line. Ligands could be differentiated as inverse agonists [i.e., 2-(4-methoxy-2-ethyl-2,3-dihydrobenzofuran-2-yl)-4,5-dihydro-1H-imidazole; RX 851062], neutral antagonists [i.e., 2-(4-hydroxy-2-ethyl-2,3-dihydrobenzofuran-2-yl)-4,5-dihydro-1H-imidazole; RX 851057], partial [i.e., 2-(4-chloro-2,3-dihydrobenzofuran-2-yl)-4,5-dihydro-1H-imidazole; RX 821008], and high-efficacy [i.e., 2-(6,7-dichloro-2,3-dihydrobenzofuran-2-yl)-4,5-dihydro-1H-imidazole; RX 821010] agonists at a precoupled alpha 2A AR state in the copresence of a G alpha oCys351Ile protein but not G alpha i2Cys352Ile protein by monitoring [35S]GTP gamma S binding responses. Neither positive nor negative efficacy was observed for these compounds by monitoring the adenylate cyclase pathway at a presumably low-affinity alpha 2A AR state. The capacity of the dexefaroxan analogs to antagonize the (-)-epinephrine-mediated [35S]GTP gamma S binding response at a G alpha oCys351Ile protein was inversely correlated with their magnitude of intrinsic activity and unrelated to their ligand binding affinity for the alpha 2A AR. On the other hand, their capacity to antagonize either (-)-epinephrine or 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline tartrate (UK 14304)-mediated inhibition of forskolin-stimulated cAMP formation was not related with the rank order of antagonist capacity for the (-)-epinephrine-mediated [35S]GTP gamma S binding response. In conclusion, these data demonstrate that certain alpha2 AR ligands that are assumed to be antagonists, may yield dissimilar pharmacological responses, dependent on the investigated agonist-stimulated effector pathway.

Synthesis of some 1-(2,4-dihydroxythiobenzoyl)imidazoles, -imidazolines and -tetrazoles and their potent activity against Candida species

Various 1-(2,4-dihydroxythiobenzoyl)imidazoles, -imidazolines and -tetrazoles were synthesized and evaluated for their in vitro antifungal activity. Compounds were prepared by the reaction of sulfinyl-bis-(2,4-dihydroxythiobenzoyl) with properly substituted azoles. The MIC values against the Candida albicans ATCC 10231 strain, the azole-resistant clinical isolates of C. albicans and non- Candida species were determined. Tetrazole derivatives were the most active against C. albicans, imidazoline derivatives against non- Candida species. All compounds showed higher activity than that of comparable drugs.

Agmatine: a mastoparan-like activity related to direct activation of heterotrimeric G proteins

We examined agmatine and imidazoline derivatives as putative ligands of trimeric G protein in rat peritoneal mast cells. Agmatine induced a concentration-dependent and pertussis toxin-sensitive secretion of histamine (exocytosis) and arachidonate. Clonidine and idazoxan had no effect. Blockage of Gβγ dimers by a specific anti-Gβ antibody inhibited exocytosis elicited by agmatine and mastoparan. The G protein antagonist [ p-Glu 5, d-Trp 7,9,10]substance P-(5–11) prevented both mastoparan- and agmatine-induced exocytosis when it was allowed to reach its intracellular targets by streptolysin-O permeabilisation. In intact cells, this response was prevented by both the removal of sialic acid residues by neuraminidase and by [ d-Pro 4, d-Trp 7,9,10]substance P-(4–11) acting at the mast cell surface. Exocytosis was restored by permeabilisation of the plasma membrane with streptolysin-O. These results suggest that agmatine might have several molecular targets, exerting its neurotransmitter function at low concentrations (i.e., with high affinity) through membrane receptors and at high concentrations (i.e., with weak affinity) through direct G protein activation.

Update on rilmenidine: clinical benefits

Rilmenidine is an imidazoline derivative that appears to lower blood pressure (BP) by an interaction with imidazoline (I 1) receptors in the brainstem (and kidneys). Rilmenidine is as effective in monotherapy as all other first-line classes of drugs, including diuretics, β-blockers, angiotensin converting enzyme (ACE) inhibitors, and calcium antagonists. It is well tolerated and can be taken in combination for greater efficacy. Sedation and dry mouth are not prominent side effects and withdrawal hypertension is not seen when treatment is stopped abruptly. Recently, in addition to a reduction in BP, this agent has been shown to improve glucose tolerance, lipid risk factors, and insulin sensitivity. These changes would be consistent with a reduction in long-term cardiovascular risk, as would recently described actions on the heart (reducing left ventricular hypertrophy) and the kidney (reducing microalbuminuria). Although no data are yet available from prospective long-term outcome studies, rilmenidine could represent an important new development in antihypertensive therapy and the prevention of cardiovascular disease.

A novel chromatographic solid support with immobilized unilamellar liposomes for model analysis of solute–membrane interaction: comparison with analysis using immobilized artificial membranes and free liposomal membranes

For chromatographic system model analysis of solute–membrane interactions, large unilamellar liposomes can be stably immobilized in the pores of gel beads by avidin–biotin specific binding. Interaction of several β-blockers, imidazoline derivatives and p-alkylphenols with the immobilized liposomal membranes was shown by their elution profiles. The solutes showed significant retardation on the liposome column compared to the liposome-free column, confirming that the solutes only interact with immobilized liposomes. The membrane partition coefficient ( K LM) of the solutes can be conveniently determined by immobilized liposome chromatography (ILC). Compared with the conventional method for determining the membrane partition coefficient in liposome suspensions, the ILC method is simple and rapid in determining the K LM values of many solutes. Compared with the use of immobilized artificial membranes (IAMs), the immobilized unilamellar liposomes used for ILC runs are more physically similar to fluid lipid bilayers. In addition, the K LM values of several β-blockers correlated well with drug permeability through Caco-2 cells.

Glucose-induced insulin secretion is potentiated by a new imidazoline compound.

Sulfonylureas stimulate insulin secretion independent of the blood glucose concentration. This can lead to hypoglycaemia in type 2 diabetic patients. Over the last years a number of imidazoline derivatives have been identified that stimulate insulin secretion in a more glucose-dependent way. In agreement with this, our aim was to generate imidazoline derivatives with a potential for the treatment of type 2 diabetic patients. We developed the compound 2-[4-(4-chlorophenyl)-3-(2-methoxyethoxy)-2-naphthalenyl]-4,5-dihydro-1-H-imidazole monohydrochloride (LY389382) with an imidazoline moiety and investigated its effects on glucose-dependent insulin secretion in a beta-cell line, isolated rat islets and in vivo. We could demonstrate that LY389382 induces insulin secretion in MIN6 cells and rat islets in a glucose-dependent manner (EC50=1.1 microM and 0.3 microM, respectively). Furthermore during hyperglycaemia LY389382 increased insulin secretion in a dose-dependent manner in healthy rats, whereas the compound had no effect at euglycemia in a tenfold higher dosage. After 7 days of treatment of Zucker Diabetic Fatty [ZDF/ (Gmi/fa)] rats with LY389382 with a dose of 15 mg/kg twice daily the blood glucose concentration was reduced from 22.7 +/- 1.7 mM to 16.6 +/- 2.3 mM. During the same time period the glucose concentration increased from 21.7+/-1.7 mM to 28.9 +/- 1.3 mM in the vehicle-treated group (P<0.05). The drop of the insulin level was also inhibited by LY389382 in ZDF rats. In contrast to other well-characterised imidazolines that have been shown to induce a glucose-dependent insulin secretion only within a limited range of concentrations, LY389382 stimulates insulin secretion over a concentration range of at least two log units in a glucose-dependent manner. These data suggest that this imidazoline compound has a potential for the treatment of type 2 diabetes.

Evidence for a non-adrenoceptor, imidazoline-mediated contractile response to oxymetazoline in the porcine isolated rectal artery.

Imidazoline derivatives are known to elicit responses through both alpha(2)-adrenoceptor and non-adrenoceptor, imidazoline sites, though as yet there are no examples of the latter on vascular smooth muscle. In the presence of 0.3 microM prazosin, neither UK-14304 (0.01 - 3 microM) nor oxymetazoline (0.01 - 30 microM) caused a significant contraction of the porcine isolated rectal artery, a preparation with a low density of alpha(2)-adrenoceptors. In the presence of a combination of U46619 and forskolin, however, both agonists produced concentration-dependent contractions. Pretreatment with phenoxybenzamine (3 microM) abolished responses to UK-14304, but left those elicited by oxymetazoline largely unaffected. The putative I(3) imidazoline antagonist 2-(2,3 dihydro-2-benzofuranyl)-2-imidazole (KU-14R, 10 microM) caused a 6 fold rightward displacement of the phenoxybenzamine-insensitive concentration - response curve to oxymetazoline. Our data indicates that non-adrenoceptor, imidazoline sites, pharmacologically similar to the I(3) imidazoline site on islet cells, mediate vasoconstriction in the porcine isolated rectal artery.

Inhibition by Clonidine of the Carbachol-Induced Tension Development and Nonselective Cationic Current in Guinea Pig Ileal Myocytes

Effects of Clonidine, an imidazoline derivative as well as a 2-adrenoceptor agonist, on carba-chol (CCh)-evoked contraction in guinea pig ileal smooth muscle were studied using isometric tension recording. To investigate the cellular mechanisms of the inhibitory effect of clonidine, its effects on CCh-evoked nonselective cationic current (Icch), voltage-dependent Ca2+ current (Ica) and voltage-dependent K+ current (Ik) was also studied using patch-clamp recording techniques in single ileal cells. Clonidine inhibited the contraction evoked by CCh (1 /M) in a concentration-dependent manner with an IC50 valve of 61.7 ± 2.5 μ M. High K+ (40 mM)-evoked contraction was only slightly inhibited even when clonidine was used at 300 /M. Externally applied clonidine inhibited Icch dose-dependently with an IC50 of 42.0 ± 2.6 /M. When applied internally via patch pipettes, clonidine was without effect. An Icch-like current induced by GTPγS was also inhibited by bath application of clonidine. None of KU14R and BU224, both imidazoline receptor blockers, and yohimbine, an α2-adrenergic blocker, significantly affects the inhibitory effect of clonidine on Icch. Clonidine (300 μ M) only slightly decreased membrane currents flowing through voltage-gated Ca2+ channels or K+ channels. These data indicate that clonidine relaxes smooth muscle contraction produced by muscarinic receptor activation and suggest that the effect of clonidine seems due mainly to inhibition of Icch via acting directly on the involved cationic channel.

Reactivity properties of derivatives of 2‐imidazoline: an ab initio DFT study

AbstractThe structural and electronic properties of a series of imidazoline (I) derivatives R1‐I‐R2 have been studied by means of density functional theory. The chosen compounds have different chain lengths (R1) and pendant (R2) groups, where R1=CH3, (CH2)nCH3 (n=2,4,…,16) and R2=H, CH3, C2H5, C3H7, C2H5OH, C2H5NH2, C2H5SH, C2H5COOH, and C2H5Cl. All‐electron calculations were carried out by means of the Gaussian‐98 program. Natural and Mulliken population analysis were determined for each of the neutral and charged molecules. The reactivity was analyzed in terms of the Fukui indices. The results indicate a high reactivity for both the tertiary (showing the biggest) and the iminic nitrogen atoms of the imidazoline ring. Although the N site of the pending groups has a much lower reactivity, this is significantly increased when a sulfur atom replaces it. In general, the reactivity of the N atoms of the ring depends significantly on the substituents. As expected, the frontier molecular orbitals, highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), also describe the reactivity behavior. As the size of the R1 chain increases, the two N atoms of the ring increase their nucleophilic character, since the HOMOs become more highly located. The obtained results help to explain the observed increased activity of these derivatives when they are used as inhibitors of corrosion moieties on metallic surfaces. Finally, the solvent effects on the ground‐state geometry were studied for one of the most promising reactive imidazolines; for which its interaction with an iron oxide surface was also addressed. © 2001 John Wiley &amp; Sons, Inc. Int J Quantum Chem, 2001

Stimulation of insulin secretion in clonal BRIN-BD11 cells by the imidazoline derivatives KU14r and RX801080

The imidazoline derivatives KU14R and RX801080 have each been reported to antagonize imidazoline-stimulated insulin secretion. This study investigated the effects of a range of concentrations of both KU14R and RX801080 on insulin secretion from the clonal pancreatic beta cell line, BRIN-BD11. In the presence of a stimulatory (8.4 mm ) glucose concentration, both KU14R (50–200 μm;P< 0.01 to P< 0.001) and RX801080 (50–200 μm;P< 0.01 to P< 0.001) were found to dose-dependently stimulate insulin secretion. The imidazoline efaroxan (200 μm) stimulated insulin secretion (P< 0.001) from BRIN-BD11 cells. This insulinotropic effect was significantly augmented by KU14R (100–200 μm;P< 0.01 to P< 0.001) and RX801080 (200μm ;P< 0.05). Insulin secretion from BRIN-BD11 cells was also stimulated by the novel guanidine derivative BTS 67 582 (200 μm;P< 0.001). This secretagogue action was augmented both by KU14R (25–200 μm;P< 0.001) and by RX801080 (25–200μm ;P< 0.05 to P< 0.001). It is concluded that, rather than acting as antagonists of imidazoline-induced insulin secretion, the imidazoline derivatives KU14R and RX801080 are themselves potent insulinotropic agents.

Imidazoline Receptor Contributes to Ion and Water Transport across the Intestine of the Eel Acclimated to Sea Water

Guanabenz, an I2-imidazoline-related compound with high affinity for intestinal membrane of the eel (), enhanced the transepithelial potential difference (PD) and short-circuit current (Isc) from serosa to mucosa after pretreatment with isobutylmethylxanthine (IBMX), serotonin (5-HT) and methacholine (MCh). The mucosal effect of guanabenz was not mimicked by adrenaline, indicating that the mucosal guanabenz binding site is not adrenoceptors. The mucosal guanabenz enhanced the Isc in a concentration-dependent manner. Similar enhancement in the Isc was also obtained after addition of other imidazoline derivatives such as ST93, clonidine, ST91, naphazoline and UK14,304 into the mucosal fluid. On the other hand, the effect of guanabenz was completely blocked by mucosal RX821002 or efaroxan, another imidazoline derivatives. Since some imidazoline derivatives act as agonists and others as antagonist, there must exist imidazoline receptor on the mucosal side of the eel intestine. Accompanied by an increase in the PD, NaCl and water absorption across the intestine was also enhanced by mucosal guanabenz. To search for endogenous ligands for the imidazoline receptor, luminal fluid in the intestine of the seawater eels was collected. However, most luminal fluid was ineffective. Only one among 10 samples showed guanabenz-like activity, suggesting that the endogenous ligands is secreted into the lumen under restricted condition alone.

Synthesis, structure and antiaggregatory effects of some N-(4,5-dihydro-1 H-imidazol-2-yl)indoles

A series of 1-(4,5-dihydro-1 H-imidazol-2-yl)indole derivatives was prepared in order to evaluate their antiaggregatory activity in human platelets. The compounds 4a– m were prepared by reacting N-aryl- N-(4,5-dihydro-1 H-imidazol-2-yl)hydroxylamines ( 2a– d) with monosubstituted acetylene derivatives 3a– b. Imidazoline derivatives 4 were further acetylated or sulfonylated to give amides 5a– c and sulfonamides 6a– c and 7a– c, respectively. Eight compounds were taken as representative aryliminoimidazoline analogs. Among them only one, 4m, showed a good concentration-dependent action against the primary or α 2-adrenoreceptor mediated phase of noradrenaline-induced aggregation in platelets.

Positive Inotropic Effects of Imidazoline Derivatives Are Not Mediated via Imidazoline Binding Sites but α1-Adrenergic Receptors

Imidazoline-binding sites are non-adrenergic receptors and classified into I11/I2 subtypes. There is strong evidence that I1-binding sites, located in the rostro-ventrolateral medulla, are involved in regulation of blood pressure. However, less is known about the peripheral participation of I1-binding sites in cardiovascular reactions. Therefore, the aim of this study was to investigate whether specific imidazoline derivatives influence myocardial contractility and whether imidazoline binding sites are expressed in rat heart. Agmatine, clonidine and idazoxan failed to alter inotropy in left atria within the whole concentration range tested (1 nM - 100 microM), whereas cirazoline (1- 100 microM) and moxonidine (100 microM) increase inotropy by about 20-30%. After preincubation with the alpha1-adrenoceptor antagonist prazosin, the cirazoline and moxonidine stimulated inotropy was antagonized, indicating more an alpha1-adrenergic and less an imidazoline binding site mediated mechanism. Radioligand-binding studies in membranes of left ventricles using [3H]-clonidine to specify I1-binding yielded KD values of 12.7 microM, confirming the functional results of an absence of I1-binding sites in ventricles of rats. However, the existence of low affinity I2-binding sites determined by [3H]-idazoxan labeling could not be excluded since a KD of 0.5 microM was calculated and since competition studies with guanabenz (Ki = 0.1 microM), clonidine (Ki = 58.1 microM) and moxonidine (Ki = 129 microM) confirmed the specificity of the I2-binding.

Spectroscopic conformational study of PMS 952, a specific imidazoline ligand. Experimental results

X-ray analysis of PMS 952 displays two kinds of very strong hydrogen bonds, an intramolecular one stabilizing the conformer A and an intermolecular one that associates conformers A to form two infinite chains. The 1H NMR study of vicinal coupling constants based on dihedral angle values, evidences that PMS 952 takes up an eclipsed conformation, in CCl4 and CDCl3 solutions, closely related to the conformation in solid state. Deuterium exchange in methanol-d4 points out the presence of a tautomeric form. However, as there is spectral evidence neither from NMR nor from FTIR studies for such a tautomer, this specie cannot be taken into account to explain the complexity of the FTIR spectra. NMR data also reveal that the imidazoline ring freely rotates while FTIR analysis allows characterizing two conformers (A and B), with lifetime shorter than NMR time scale. These two conformers are stabilized by two different intramolecular H-bonds. Taking into account that conformer A could exist in two states (monomer A and (A)n-chains), an equilibrium between A, (A)n, and B entities allowed the assignment of all main bands of the IR spectra, assigned to vNH, vOH, vCH, and vCN modes. The strength of hydrogen bonds is solvent dependent. Polar solvents, either proton donor or acceptor stabilized the conformer A, while CCl4 favors the conformer B.Key words: hydrogen bonds, X-ray, NMR, FTIR, imidazoline derivative.

Imidazoline derivatives and agmatine induce histamine release from the rat stomach

Strips from rat glandular stomach were used to investigate whether the imidazoline derivatives clonidine, tolazoline and BDF 6143 (4-chloro-2(2-imidazolin-2-ylamino)-isoindoline) and the guanidine derivative agmatine are able to release histamine from histamine-storing cells. Histamine was detected and quantified by HPLC. Clonidine, tolazoline and agmatine concentration-dependently induced a release of histamine from the gastric strips, whereas BDF 6143 was ineffective. However, BDF 6143 abolished the release-inducing effect of clonidine and agmatine. It is concluded that imidazoline and guanidine derivatives can induce histamine release from histamine-storing cells in the stomach by a specific mechanism (possibly via imidazoline receptors) which in turn might lead to a relevant increase in gastric acid secretion.

Analytical application of atomic emission and atomic absorption spectrometry for the determination of imidazoline derivatives based on formation of ion-associates with sodium cobaltinitrite and potassium ferricyanide

Ion-association complexes of Naphazoline HCl (I), Tolazoline HCl (II) and Xylometazoline HCl (III) with [Co(NO2)6]3− and [Fe(CN)6]3− were precipitated and the excess of the unreacted iron or cobalt comples was determined. A new method using atomic emission and atomic absorption spectrometry for the determination of the above drags in pure solutions and in pharmaceutical preparations is given. The drugs have been determined in the ranges 0.98–14.76, 0.78–11.80 and 1.12–16.80 μg/ml solutions of I, II and III. respectively, using [Co(NO2)6]3−], with mean relative standard deviations of 0.4–1.5% and 1.92%–19.68, 1.52–5.68 and 2.24–22.4 μg/ml solutions of I, II and III, respectively using [Fe(CN)6]3− with mean relative standard deviations of 0.6–1.6%. The recovery values of 98.12–101.26% indicate high precision and accuracy.

Theoretical and experimental studies of structure and inhibition efficiency of imidazoline derivatives

The purpose of this paper is to provide information on the electron configuration of several imidazoline inhibitors by the quantum chemical calculation and to seek correlation between molecular structure and behavior of corrosion inhibition. Three imidazoline derivatives with different electron-releasing substituents were designed by quantum chemical study. On the basis of calculated results, the inhibition efficiency is predicted as in following order: compound III>II>I. These compounds were synthesized and measured by weight loss and electrochemical methods. Theoretical prediction is in good agreement with experimental results. Based on the theoretical and experimental results, it is concluded that electron donor group introduced, particularly, the substituent group with conjugated system, to imidazoline ring will improve corrosion inhibition efficiency of imidazoline derivatives.