Imidazoline Derivatives Research Articles

Relationship between α2-Adrenergic Receptors and Imidazoline/Guanidinium Receptive Sites

Publisher Summary Compounds such as the α 1 -adrenergic receptor (AR) agonist/ α 2 -AR antagonist cirazoline, the α 2 -AR antagonist idazoxan, the α 2 -AR agonist guanabenz, the ion transport inhibitor amiloride, and other structurally related ligands that have an imidazoline or guanidinium moiety elicit a number of pharmacological effects. Although such ligands interact with known receptor systems, some of their functional effects are pharmacologically illdefined, such as their centrally mediated effects on blood pressure and the ability of certain imidazoline derivatives to augment glucose-induced insulin secretion from pancreatic β cells. Indeed several studies indicate that these molecules interact with distinct membrane-bound proteins variously termed imidazoline/ guanidinium receptive sites (IGRS), imidazoline binding proteins, I 1 and I 2 receptors, imidazoline receptors, nonadrenergic imidazoline binding sites, or imidazole receptors. These sites share the common property of not recognizing endogenous agonists for known monoamine receptors, but subgroups of these binding sites differ in their ligand recognition properties in various tissues. The synthetic ligands recognized by imidazoline binding proteins elicit several cell responses; however, the signaling pathways involved and the relative importance of these proteins in these events are unclear.

Presynaptic imidazoline receptors and alpha 2-adrenoceptors in the human heart: discrimination by clonidine and moxonidine.

The involvement of presynaptic alpha 2-autoreceptors and imidazoline receptors in the modulation of noradrenaline release was investigated in strips from human atrial appendages preincubated with [3H]noradrenaline and superfused with medium containing desipramine and corticosterone. Electrical impulses were applied transmurally at 2 Hz. The imidazoline derivatives moxonidine and clonidine reduced to evoked tritium overflow in a concentration-dependent manner. Moxonidine was 18-fold more potent than clonidine. The concentration-response curve for moxonidine, but not for clonidine was shifted to the right by the alpha 2-adrenoceptor antagonist rauwolscine. The apparent pA2 value of rauwolscine against moxonidine was 8.41. An inhibitory effect was also observed for the imidazoline derivative BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline), a mixed alpha 2-adrenoceptor antagonist/imidazoline receptor agonist; BDF 6143 was about 2-fold more potent than clonidine. Rauwolscine (1 microM) did not substantially shift the concentration-response curve of BDF 6143. It is concluded that noradrenaline release in the human atrium is inhibited not only via presynaptic alpha 2-autoreceptors but also via presynaptic non-I1, non-I2 imidazoline receptors. The failure of rauwolscine to antagonize the inhibitory effect of clonidine suggests that clonidine preferentially stimulates the presynaptic imidazoline receptors; the alpha 2-adrenoceptor component of its action is probably suppressed by an inhibitory interaction between the two receptors. In contrast, moxonidine acts via presynaptic alpha 2-autoreceptors, leaving the presynaptic imidazoline receptor unaffected.

Imidazoline compounds stimulate insulin release by inhibition of K(ATP) channels and interaction with the exocytotic machinery.

A novel imidazoline compound, RX871024, was used to investigate the mechanisms by which imidazoline derivatives promote insulin secretion in rat pancreatic beta-cells and HIT T15 cells. RX871024 stimulated insulin release from rat pancreatic beta-cells and HIT T15 cells in a glucose-dependent way. This effect was not related to alpha2-adrenergic, I1-, and I2-imidazoline receptors. RX871024 promoted insulin release by at least two modes of action. One included an increase in cytoplasmic free Ca2+ concentration ([Ca2+]i), subsequent to blocking of ATP-dependent K+ channels, membrane depolarization, and activation of voltage-dependent Ca2+ channels. The other, a more distal effect of imidazoline, affected the exocytotic machinery and was unrelated to changes in membrane potential and [Ca2+]i. The mechanism of RX871024-induced insulin release was dependent on protein kinases A and C. The sensitizing effect of a low dose of RX871024 on glucose-induced insulin secretion suggests that imidazoline compounds of this kind may constitute the basis for development of a new class of oral hypoglycemic agents.

Synthesis and biological activities of new 2-imidazoline derivatives

Synthesis and biological activities of new 2-imidazoline derivatives

Effects of imidazoline antagonists of α 2-adrenoceptors on endogenous adrenaline-induced inhibition of insulin release

We studied the effects of adrenoceptor antagonists and imidazoline derivatives on endogenous adrenaline-induced inhibition of insulin release in anesthetized rats. The intracerebroventricular injection of neostigmine increased plasma levels of catecholamines and glucose but not insulin. Pretreatment with an i.p. injection with phentolamine caused a dose-dependent increase in insulin secretion. When atropine was coadministered with phentolamine, the phentolamine-induced increase in insulin secretion was inhibited. Neither phentolamine nor atropine affected plasma levels of catecholamine. Yohimbine and idazoxan, which are α 2-adrenoceptor antagonists, and tolazoline, a non-selective α-adrenoceptor antagonist, also reversed adrenaline-induced inhibition of insulin secretion. Phenoxybenzamine, prazosin, propranolol, and antazoline, an imidazoline without α 2-adrenoceptor activity, did not affect insulin levels. When agents were preinjected i.p. in rats that were given saline into the third cerebral ventricle, phentolamine and antazoline, but not yohimbine and idazoxan, increased plasma levels of insulin. The results suggest that the inhibition of insulin release induced by adrenaline was reversed by antagonism of α 2-adrenoceptors. Phentolamine and antazoline, both of which are imidazoline derivatives, induced insulin secretion independently of the adrenoceptors only under the resting conditions.

A rationale for the selection of nasal decongestants in lacrimal drainage surgery.

Adequate hemostasis during lacrimal drainage surgery affects the success of the operation. Nasal decongestants, which are sympathomimetric agents including sympathomimetic amines and imidazoline derivatives, help to decrease bleeding. Certain of the imidazoline derivatives--oxymetazoline and xylometazoline--are potent and long-acting agents that have many of the same adrenergic effects as cocaine. Their use as an alternative to cocaine provide adequate hemostasis with less adverse reactions than cocaine. The authors recommend premedication of the nasal mucosa with oxymetazoline or xylometazoline before lacrimal drainage surgery for obtaining maximal nasal mucosal decongestion.

3H]cirazoline as a tool for the characterization of imidazoline sites.

Recent studies have shown that cirazoline, an alpha 1-adrenoceptor agonist, has greater affinity than do other imidazoline or guanidinium compounds at imidazoline recognition sites. In this report we used [3H]cirazoline as a probe to characterize imidazoline recognition sites present in membrane homogenates of rat brain and kidney as well as pancreatic beta HIT T15 cells. Specific binding of [3H]cirazoline to these various homogenates was saturable and reversible and was resolved into two classes of high affinity binding sites. Competition inhibition studies of [3H]cirazoline binding to these different membrane preparations were performed with alkaloid, phenylethylamine, imidazoline, and guanidinium compounds. Catecholamines and non-imidazoline adrenoceptor ligands such as epinephrine, benextramine, prazosin, propranolol, rauwolscine, or adrenoceptor ligands such as epinephrine, benextramine, prazosin, propranolol, rauwolscine, or yohimbine did not compete with [3H]cirazoline (Ki > 10 microM). Under our experimental conditions, only guanidinium and imidazoline derivatives had high affinities for [3H]cirazoline binding sites. Unlabeled cirazoline, clonidine, bromoxidine, idazoxan, and amiloride had the highest affinities with this respective rank order. These results suggest that [3H]cirazoline is a novel high affinity radioligand that specifically labels nonadrenergic imidazoline-guanidinium sites in the brain, kidney, and beta cells. Furthermore, the obtained rank order of inhibition suggests that [3H]cirazoline binding does not distinguish between I1 and I2 sites. In addition, we compared the specific binding of [3H]cirazoline with that of the alpha 2-adrenoceptor antagonist [3H]rauwolscine in chinese hamster ovary (CHO) cell lines stably expressing human alpha 2C2-, alpha 2C4-, and alpha 2C10-adrenoceptor subtypes. Using [3H]rauwolscine as a probe, each of these transfected cell lines expressed high levels for the three different alpha 2-adrenoceptor subtypes (Bmax values were between 2 and 7 pmol.mg-1 protein). In contrast, none of these cell lines displayed measurable imidazoline recognition sites. In summary, [3H]cirazoline is a novel high affinity radioligand that specifically labels imidazoline recognition sites without significant alpha- or beta-adrenoceptor binding. Furthermore, our results using alpha 2-adrenoceptor transfected cells confirm that the imidazoline recognition sites and each of the cloned alpha 2-adrenoceptor subtypes represent distinct macromolecular entities.

Influence of Imidazolines on Catecholamine Release in Pithed Spontaneously Hypertensive Rats

The actions of the imidazoline derivatives clonidine, moxonidine, and rilmenidine and of the recently discovered clonidine-displacing substance agmatine on stimulation-induced norepinephrine overflow and epinephrine release were studied in pithed spontaneously hypertensive rats. All three imidazolines dose-dependently decreased norepinephrine overflow and led to an increase in epinephrine release when the highest dose of each compound was injected. The alpha 2-adrenoceptor antagonist rauwolscine shifted the dose-response curves of plasma norepinephrine concentrations to higher levels. Agmatine did not change norepinephrine overflow but increased epinephrine release into plasma after the highest dose administered. It is concluded that the investigated imidazolines decrease norepinephrine overflow via presynaptic alpha 2-adrenoceptors, whereas epinephrine release is mediated through putative imidazoline receptors on the adrenal medulla.

Inhibitory presynaptic imidazoline receptors on sympathetic nerves in the rabbit aorta differ from I1- and I2-imidazoline binding sites

The involvement of imidazoline receptors in modulation of noradrenaline release was investigated in the rabbit aorta preincubated with [3H]noradrenaline and superfused with physiological salt solution containing cocaine, corticosterone and propranolol. After blockade of alpha 2-autoreceptors by rauwolscine, the electrically evoked tritium overflow was inhibited by various imidazolines and guanidines. The rank order of potency was BDF 7579 (4-chloro-2-isoindolinyl) guanidine) > or = BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline) > BDF 6100 [2-(2-imidazolin-2-ylamino)-isoindoline] > clonidine > ST587 (2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine nitrate) > or = cirazoline > tolazoline > idazoxan > phentolamine. Comparison of the potencies of these drugs with those previously found for the presynaptic imidazoline receptors in the rabbit pulmonary artery revealed a very good correlation. In contrast, no positive correlation was found with their affinities for the I1- and I2-imidazoline binding sites in bovine adrenal medullary membranes and with their lipophilicity (log P values). The electrically evoked tritium overflow was also inhibited by the recently identified endogenous imidazoline receptor ligand agmatine, but was not affected by amiloride. In further series of experiments, the ability of putative antagonist at presynaptic imidazoline receptors to counteract the inhibitory effect of imidazoline derivatives was determined. Amiloride, imidazole-4-acetic acid and 1-benzylimidazole did not attenuate the inhibitory effect of BDF 6143 on the electrically evoked tritium overflow. In contrast, rauwolscine antagonized the inhibitory effect of various imidazolines; rauwolscine was clearly less potent in antagonizing the effect of clonidine, BDF 6143 and cirazoline (apparent pA2 6.48-7.32) than in antagonizing that of oxymetazoline and moxonidine (apparent pA2 8.33 and 8.12, respectively). In a final series of experiments, BDF 6143 (under the conditions applied a selective agonist at presynaptic imidazoline receptors) proved to be considerably less potent in inhibiting tritium overflow evoked by high K+ than by electrical stimulation, whereas moxonidine (in rabbit aorta a selective agonist at presynaptic alpha 2-adrenoceptors) exhibited similar potency in inhibiting the overflow evoked by both methods of stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Binding of [ 3H]cirazoline to an imidazoline site in rat brain and kidney membranes

Two classes of high-affinity sites for [ 3H]cirazoline were characterized in rat brain and kidney membranes. In both tissues, the binding parameters for the high- and low-affinity sites are similar with B max values of ∼ 50 fmol/mg protein, K d ∼ 0.6 nM and B max ∼ 470 fmol/mg protein, K d ∼ 11 nM respectively. Inhibition studies of [ 3H]cirazoline binding to the lower affinity site revealed that only guanidinium or imidazoline derivatives compete with the specific binding of this radioligand. Our results suggest that [ 3H]cirazoline could be used as a novel ligand to label the non-adrenergic imidazoline-preferring sites.

1,2-Disubstituted imidazolines with heterocyclic fragments as antimicrobial additives for jet fuels

The most promising and convenient method for protecting hydrocarbon fuels against damage by microorganisms is the use of antimicrobial additives that are effective for extended periods in the storage and transportation of fuels. Imidazoline derivatives manifest high biocidal activities in petroleum distillate fuels, with the activity depending considerably on the nature and structure of the radicals linked to the imidazoline ring. One example of a highly effective additive is AID 9-12, the basic components of which are 1,2-disubstituted imidazolines obtained by the condensation of polyethylenepolyamines with an n-C{sub 9} - C{sub 12} fraction of synthetic fatty acids. At low concentrations in jet fuels, this additive exhibits high activities against microbial damage without having any adverse effects on the physicochemical or service properties of the fuels. Also effective as antimicrobial additives for jet fuels are imidazolines with sterically hindered phenol fragments or with naphthyl or benzyl radicals. In our search for effective antimicrobial additives, we have investigated a series of 1,2-disubstituted imidazolines with heterocyclic fragments. In this paper, we report the results of our investigation.

FC42 synthesis and biological activity of novel classes of 2-imidazoline derivatives

FC42 synthesis and biological activity of novel classes of 2-imidazoline derivatives

Inhibition by imidazoline and imidazolidine derivatives of glibenclamide-sensitive K + currents in Xenopus oocytes

The effects of imidazoline and imidazolidine derivatives on glibenclamide-sensitive K + currents induced by the novel K + channel opener, Y-26763 ((+)-(3 S,4 R)-4-( N-acethyl- N-benzyloxyamino6-cyano-3,4-dihydro-2,2-dimethyl-2 H-1-benzopyran -3-ol), were investigated in voltage-clamped follicle-enclosed Xenopus oocytes. Of 14 imidazoline derivatives and seven imidazolidine derivatives tested, phentolamine, (−)-cibenzoline, (+)-cibenzoline, alinidine, oxymetazoline, antazoline, midaglizole, xylometazoline, tramazoline and ST91 (2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride) potently suppressed Y-26763-induced K + currents (IC 50 < 80 μM). The compounds which lack an aromatic ring in their structure,2-methyl-2-imidazole and 2-hydrazino-2- imidazoline, did not affect the K + currents. Clonidine and idazoxan, which both bind to imidazoline-preferring binding sites with high affinity in various tissues, showed only a small inhibitory effect on Y-26763-induced K + currents (IC 50 780 μM and 955 μM, respectively). The non-imidazoline/non-imidazolidine α-adrenoceptor antagonists, WB-4101 (2-(2,6-dimethoxy-phenoxy-ethyl)-aminomethyl-1,4- benzodioxane hydrochloride), yohimbine and rauwolscine, showed suppressive effects on Y-26763-induced K + currents (IC 50 203 μM, 813 μM and 832 μM, respectively). Octopamine (1 mM), a non-imidazoline / non-imidazolidine α-adrenoceptor agonist, was inactive. The results suggest that (1) an aromatic ring or aromatic rings are an essential moiety for imidazoline or imidazolidine derivatives to block glibenclamide-sensitive K + currents in oocytes, and (2) the K + current-blocking ability of imidazolines and imidazolinenes is related to the alkylation of the benzene ring and the existence of a tertiary amine structure. The K + current-blocking effects of imidazolines or imidazolidines may not be mediated by α-adrenoceptors, at least in follicle-enclosed Xenopus oocytes.

Effects of imidazolines on noradrenaline release in rat isolated kidney.

The aim of the present study was to investigate whether or not activation of imidazoline receptors modulates noradrenaline release in the rat isolated kidney. Kidneys were pre-exposed to 3H-noradrenaline and the renal nerves were stimulated with 6 pulses at 100 Hz. The stimulation induced (S-I) outflow of radioactivity was taken as an index of endogenous noradrenaline release. The imidazoline derivatives clonidine (1-1000 nmol/l) and moxonidine (10-1000 nmol/l) inhibited S-I outflow of radioactivity with an EC50 of 6.8 nmol/l and 62.5 nmol/l and a maximum of 88% and 97%, respectively. The concentration response curves for clonidine and moxonidine were shifted to the right by the selective alpha 2-adrenoceptor antagonist rauwolscine (0.1 mumol/l) in a parallel manner with identical pKB's of 8.52 and 8.46, respectively. Furthermore, the alpha-adrenoceptor agonist (-)-alpha-methylnoradrenaline (0.1-30 nmol/l), which has no affinity for imidazoline binding sites, inhibited S-I outflow of radioactivity with and EC50 of 2.4 nmol/l and a maximum of 94%. Rauwolscine (0.1 mumol/l) again shifted the concentration response curve for this alpha-adrenoceptor agonist to the right with a pKB of 8.40. Moreover, the selective alpha 2-adrenoceptor antagonist 2-[2-(2-methoxy-1,4- benzo-dioxanyl)]imidazoline HCl (RX821002, 0.01 mumol/l) shifted the concentration response curves for clonidine and moxonidine to the right with pKB's of 9.46 and 9.18, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional consequences of prejunctional receptor activation or blockade in the iris.

The iris is innervated by nerves of the sympathetic, parasympathetic, and sensory nervous systems. The terminal nerve fibres are endowed with prejunctional receptors which modulate neurotransmitter release. Activation or blockade of prejunctional receptors by drugs may have an influence on iris smooth muscle tone. Several findings are in favour of the hypothesis that prejunctional receptors may be involved in regulation of iris smooth muscle tone and/or pathophysiological events. (i). Release of acetylcholine from parasympathetic nerves of guinea-pig iris sphincter evoked by electrical stimulation is subject to autoinhibition via prejunctional M2 muscarinic receptors, and the release can be enhanced by M2 selective antagonists such as methoctramine or gallamine. Concomitantly with the increased neurotransmitter release, the sphincter contraction is enhanced in the presence of M2 antagonists, since the postjunctional muscarinic receptors (presumably M3, or at least not M2) are not simultaneously blocked. Unlike the non-selective blocker atropine, M2 antagonists are not expected to cause mydriasis but rather miosis. (ii). Sensory nerves are involved in pathophysiological events following ocular irritation. Release of substance P and/or neurokinin A from sensory nerves of rabbit iris is followed by a non-adrenergic-non-cholinergic iris sphincter contraction (mediated by NK1 and NK3 receptors) which can be used to estimate sensory neurotransmitter release. Exocytotic release of the sensory neurotransmitters is inhibited by activation of alpha 2B-adrenoceptors and probably also via putative prejunctional imidazoline receptors. Alpha-adrenoceptors are stimulated by oxymetazoline and other imidazoline derivatives (which are agonists at imidazoline receptors) leading to a reduction of sensory neurotransmitter release, as evident from a decrease in evoked sphincter contraction. Imidazolines in eye drops may not only cause relief in ocular inflammation due to postjunctional vasoconstriction but also possibly due to a prejunctional effect, a reduction of sensory neurotransmitter release. Reinforcement of inflammation due to release of sensory neurotransmitters may thus be prevented.

Neue Entwicklungen auf dem Gebiet der Wäscheweichspuüler

Particularly in Germany and Holland, the most common softening component in commercial fabric softeners, ditallow dimethyl ammonium chloride (DTDMAC) has been replaced, by imidazoline derivatives for aquatoxicity reasons, later on by derivatives of 2,3-dihydroxypropyl-1-trimethyl-ammonium chloride and particularly by quaternised ditallow fatty acid esters of triethanolamine, known as esterquats. In spite of the excellent biodegradability and good aquatoxicity of esterquats we attempted to develop a constituent which effects softnening in a synergistic way with esterquats. So the required amount of esterquat could be decreased. Quaternisation of triethanolamine ditallow fatty acid ester by dimethylsulphate in 30% wt. propoxylated palm oil instead of 10% wt. of 2-propanol, as usual, gives an esterquat with a comparable softening effect on textiles using the same overall amount in a relevant concentration range. Propoxylated palm oil thus does not only act as a solvent, but has additionally a synergistic softening effect together with the esterquat. Propoxylated palm oil has good biodegradability and toxicological acceptability, and thus satisfies all requirements on a constituent of fabric softeners

Synthesis of amino acids and related compounds. 42. A novel transformation of imidazolines into 2,4,6-trisubstituted pyrimidine derivatives

2,5-Diaryl-4-(chloromethyl)imidazoline derivatives 5a-g, obtained from N-acyl-α-amino ketone derivatives 1, were rearranged with sodium hydride in dimethylformamide. Spontaneous air oxidation led to 2,4-di- and 2,4,6-triarylpyrimidine derivatives 6a-g in good yields

Evidence of increased non-adrenoceptor [ 3H]idazoxan binding sites in the frontal cortex of depressed suicide victims

Hyperactivity of inhibitory ct2-adrenoeeptors has been postulated in the pathogenesis of endogenous depression (Garefa-Sevilla 2989). This hypothesis was initially supported by the finding that depressed patients show supersensitive ~2-adrenoceptors in blood platelets (Garcfa-Sevilla et al 1986; Piletz et al 1991) and recently by the direct evidence of an increased number and affinity of o2-adrenoceptors ([3H]clonidine, [3H]UK 24304 and [3H]idazoxan binding) in the brain of depressed suicide victims (M~ana et al 1992). These imidazoline derivatives not oldy possess high affinity for the ot2-adrenoceptor but also for non-adrenoceptor imidazoli(di)ne/guanidine-pmferring sites in the human brain (Bricca et al 1989; Convents et al 2989; De Vos et al 1991). These putative imidazoline receptors are involved in central regulation of blood pressure (Tibiri~a et al 1991) and mediate inhibitory effects on norepinephrine release in sympathetic nerve terminals (G6thert and Molderings 1992', Molderings et al 1991). The aim of the present study was to examine in more detail the binding properties of [~H]idazoxan in the brain of depressed suicide victims to quantitate simultaneously ot2-adrenoceptors and non-adrenoceptor [3Hlidazoxan binding sites (NAIBS), This investigation is an extension and refinement of a particular set ofexperiments previously reported (Meana et a! !992). However, the concepts and data presented here are new.

No effect of genetic obesity and mazindol on imidazoline I 2 binding sites in the brain of Zucker rats

The density and affinity states of imidazoline I 2 binding sites as well as the density of α 2-adrenoceptors were quantitated in the brain of lean and obese Zucker rats. No significant differences were obtained between Zucker phenotypes for these receptors in the cerebral cortex and hypothalamus. Moreover, chronic treatment with the anorexic imidazoline derivative, mazindol, did not alter the density of brain imidazoline I 2 binding sites. It is concluded that this genetic model of obesity is not associated with abnormal imidazoline I 2 binding sites.

Ocular hypotensive effects of prostaglandins (PGs) and their analogs

The imidazoline-based ophthalmic drugs oxymetazoline and xylometazoline are widely used as ocular decongestants in pharmaceutical preparations. In this paper, the degradation of these drugs and the model compound 2-methyl-2-imidazoline, was studied in the presence of the vitamin B2 (Riboflavin) and visible light.The photogenerated Riboflavin electronically excited triplet state interacts with oxymetazoline and xylometazoline and as a result different free radicals and reactive oxygen species are produced. These species interact with the drugs in further steps, producing their degradation.Oxymetazoline is more easily photo-degradable than xylometazoline towards reactive oxygen species. Particularly, oxymetazoline reacts four orders of magnitude faster than xylometazoline with singlet oxygen. This fact is due to the presence of an OH-group in the benzene ring of oxymetazoline, increasing the oxidability of the drug. The degradation of xylometazoline by reactive oxygen species becomes more important as its concentration increases. This finding should warn against long-time treatments with xylometazoline. An eventual local accumulation of the drug may cause adverse effects in the ocular organ in the presence of Riboflavin. In parallel, the present results advise for a moderate precaution in relation to light exposure after topical application of the imidazoline derivatives oxymetazoline and xylometazoline.