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Pascal Bousquet - One of the best experts on this subject based on the ideXlab platform.

  • I1 receptors, cardiovascular function, and metabolism
    2016
    Co-Authors: Pascal Bousquet
    Abstract:

    When injected into the medullary site of the hypotensive action of clonidine, Imidazolines and related compounds decrease blood pressure (BP), whereas no phenylethyl-amine compounds were capable of producing such an effect at the same site. There is much biochemical and pharmacologic evidence to support the involvement of imidazoline receptors in the regulation of vasomotor tone as well as in the mechanism of action of some centrally acting antihypertensive drugs. Imidazoline-specific bind-ing sites, which do not recognize catecholamines, have been described in various tissues. Functional studies using selective antagonists have confirmed that the hypotensive effects of clonidine-like drugs are mediated, at least in part, by nonadrenergic imidazoline-specific receptors, whereas their sedative action clearly involves 2-adrener-gic receptors located in the locus coeruleus. Compared with clonidine, newer centrally acting antihypertensive drugs such as rilmenidine are more selective for imidazo-line receptors than for 2-adrenergic receptors. This selec-tivity may explain the reduced incidence of side effects of these drugs at therapeutic doses. Very recently, imidazo-line-like compounds with no affinity and no activity at 2-adrenergic receptors have become available. Some of these compounds lowered the BP when injected centrally, indicating that an action on imidazoline I1 receptors alone is sufficient to cause hypotension. Nevertheless, imidazo-line receptors and 2-adrenoceptors cooperate in the con-trol of the vasomotor tone and in the hypotensive action of centrally acting hybrid drugs (ie, drugs that bind to both types of receptor). Additional noncardiovascular effects of imidazoline-like drugs have also been described, such as insulin secretion stimulation and renal sodium reabsorp-tion inhibition. These effects may account for the long-term benefits of imidazoline selective drugs, such a

  • I1 receptors, cardiovascular function, and metabolism
    American Journal of Hypertension, 2001
    Co-Authors: Pascal Bousquet
    Abstract:

    Abstract When injected into the medullary site of the hypotensive action of clonidine, Imidazolines and related compounds decrease blood pressure (BP), whereas no phenylethylamine compounds were capable of producing such an effect at the same site. There is much biochemical and pharmacologic evidence to support the involvement of imidazoline receptors in the regulation of vasomotor tone as well as in the mechanism of action of some centrally acting antihypertensive drugs. Imidazoline-specific binding sites, which do not recognize catecholamines, have been described in various tissues. Functional studies using selective antagonists have confirmed that the hypotensive effects of clonidine-like drugs are mediated, at least in part, by nonadrenergic imidazoline-specific receptors, whereas their sedative action clearly involves α2-adrenergic receptors located in the locus coeruleus. Compared with clonidine, newer centrally acting antihypertensive drugs such as rilmenidine are more selective for imidazoline receptors than for α2-adrenergic receptors. This selectivity may explain the reduced incidence of side effects of these drugs at therapeutic doses. Very recently, imidazoline-like compounds with no affinity and no activity at α2-adrenergic receptors have become available. Some of these compounds lowered the BP when injected centrally, indicating that an action on imidazoline I1 receptors alone is sufficient to cause hypotension. Nevertheless, imidazoline receptors and α2-adrenoceptors cooperate in the control of the vasomotor tone and in the hypotensive action of centrally acting hybrid drugs (ie, drugs that bind to both types of receptor). Additional noncardiovascular effects of imidazoline-like drugs have also been described, such as insulin secretion stimulation and renal sodium reabsorption inhibition. These effects may account for the long-term benefits of imidazoline selective drugs, such as rilmenidine.

  • Imidazoline receptors in cardiovascular and metabolic diseases.
    Journal of cardiovascular pharmacology, 2000
    Co-Authors: Pascal Bousquet, Monique Dontenwill, Hugues Greney, Josiane Feldman
    Abstract:

    The site of the hypotensive action of imidazoline compounds, such as clonidine, was first identified within the rostroventrolateral part of the brainstem. Afterwards, it was shown that Imidazolines reduced blood pressure when applied in this area, whereas no catecholamine was capable of such an effect. These data led us to suggest the existence of receptors specific for Imidazolines different from the alpha-adrenergic receptors. Soon after, the existence of imidazoline binding sites (IBS) was reported in the brain and in a variety of peripheral tissues including pancreatic gland and kidney. As expected, these specific binding sites do not bind the catecholamines. The IBS are classified in two groups: the I1 type, sensitive to clonidine and idazoxan; and the I2 type, sensitive to idazoxan and largely insensitive to clonidine. Imidazoline receptors were shown to be involved in several physiological regulations and pathological processes such as hypertension, diabetes mellitus and some mood disorders. Evidence for their implication in the nervous regulation of blood pressure and in the insulin secretion control will be presented. The hypotensive effects of clonidine-like drugs involve imidazoline receptors (I1Rs), while their most frequent side-effects only involve alpha2-adrenergic receptors. A new class of centrally acting antihypertensive drugs selective for I1Rs is now available. At hypotensive doses, these drugs are devoid of significant side effects. It was shown that the good acceptability of these drugs is likely due to their selectivity for I1Rs.

  • I1-imidazoline receptors: an update.
    Journal of hypertension. Supplement : official journal of the International Society of Hypertension, 1998
    Co-Authors: Pascal Bousquet, Monique Dontenwill, Hugues Greney, Josiane Feldman
    Abstract:

    BACKGROUND The site of the hypotensive action of imidazoline compounds, such as clonidine, was first identified within the nucleus reticularis lateralis of the rostroventrolateral part of the medulla (NRL/RVLM). It was shown that Imidazolines and related substances reduced blood pressure when applied in this area whereas no catecholamine was capable of such an effect. IMIDAZOLINE-SPECIFIC BINDING: We previously suggested the existence of receptors specific for imidazoline-like compounds that differed from the alpha-adrenergic receptors. Imidazoline-binding sites were subsequently reported in the brain and in a variety of peripheral tissues, including the human kidney, and as expected these specific binding sites do not bind the catecholamines. The imidazoline-binding sites are classified into two subgroups: the I1-type, which is sensitive to clonidine and idazoxan, and the I2-type, sensitive to idazoxan and largely insensitive to clonidine. Numerous studies have confirmed the involvement of these receptors in various regulations and pathological processes, hypertension being the most notable. DRUGS Functional studies have confirmed that the hypotensive effects of clonidine-like drugs involve I1-imidazoline receptors while their most frequent side effects only involve alpha2-adrenergic receptors. Recent studies have shown that a contribution of both receptor types might be necessary to trigger the hypotensive effect of central origin. Rilmenidine, an oxazoline analogue to the Imidazolines, has been proposed as the prototype of a new class of antihypertensive drugs selective for I1-imidazoline receptors. At hypotensive doses, this drug is devoid of any significant sedative effect. As with clonidine, it evokes hypotension when injected into the NRL region and it completely displaces the [3H]clonidine bound to specific imidazoline-binding sites in human medullary membrane preparations, but it has proved more selective for cerebral imidazoline receptors than clonidine. This selectivity might explain the low incidence of side effects evoked by rilmenidine. CONCLUSION Rilmenidine is the first example of a drug exhibiting a favourable selectivity between I1-imidazoline receptors and alpha2-adrenergic receptors, for example reducing blood pressure but avoiding sedation and mouth dryness.

  • Binding of new cirazoline derivative to imidazoline receptors from human brain
    Neurochemistry international, 1997
    Co-Authors: Monique Dontenwill, Hugues Greney, J. D. Ehrhardt, P Senecheau, A. Molines, Pascal Bousquet
    Abstract:

    Imidazoline compounds are known to interact with alpha 2-adrenoceptors as well as with specific non-adrenergic binding sites. Such binding sites are present in the brain and in peripheral tissues. Hypotensive effects of Imidazolines were shown to be related to specific interaction with imidazoline binding sites within the brainstem. Heterogeneity of these sites based on differences in selectivities was reported. In order to facilitate the characterization of human brain imidazoline receptors, we synthetized new ligands by substitutions on the cirazoline phenyl ring. Affinities of these cirazoline derivatives were determined in two imidazoline binding site models, namely the human brain and the rabbit kidney. Interaction of these compounds with imidazoline binding sites from the human brain appeared more sensitive to structural variations of the imidazoline than those with rabbit kidney sites. Moreover, no correlation was found between affinities for imidazoline binding sites and those for alpha 2-adrenoceptors of the rat brain. Arylazide derivative of 2-(5-amino-2-methyl-phenoxymethyl)-imidazoline exhibited a higher affinity for human brain imidazoline binding sites than for human brain alpha 2-adrenoceptors. Photoincorporation of this azido-compound in human brain imidazoline binding sites was achieved and blockade of [3H]idazoxan imidazoline specific binding observed. These new tools may allow fine characterization of the different subtypes of imidazoline binding proteins.

Manfred Göthert - One of the best experts on this subject based on the ideXlab platform.

  • s1p receptors in pc12 and transfected hek293 cells molecular targets of hypotensive imidazoline i1 receptor ligands
    Neurochemistry International, 2007
    Co-Authors: Gerhard J. Molderings, Christiana Wolf, Ivar Von Kügelgen, Heinz Bönisch, Michael Brüss, Manfred Göthert
    Abstract:

    Abstract The present study aimed at elucidating the molecular identity of the proposed “I 1 -imidazoline receptors”, i.e. non-adrenoceptor recognition sites via which the centrally acting Imidazolines clonidine and moxonidine mediate a major part of their effects. In radioligand binding experiments with [ 3 H]clonidine and [ 3 H]lysophosphatidic acid on intact, α 2 -adrenoceptor-deficient PC12 cells, moxonidine, clonidine, lysophosphatidic acid and sphingosine-1-phosphate (S1P) competed for the specific binding sites of both radioligands with similar affinities. RNA interference with the rat S1P 1 -, S1P 2 - or S1P 3 -receptor abolished specific [ 3 H]lysophosphatidic acid binding. [ 3 H]Clonidine binding was markedly decreased by siRNA targeting S1P 1 - and S1P 3 -receptors but not by siRNA against S1P 2 -receptors. Finally, in HEK293 cells transiently expressing human S1P 3 -receptors, sphingosine-1-phosphate, clonidine and moxonidine induced increases in intracellular calcium concentration, moxonidine being more potent than clonidine; this is in agreement with the known properties of the “I 1 -imidazoline receptors”. The present results indicate that the “I 1 -imidazoline receptors” mediating effects of clonidine and moxonidine in PC12 and the transfected HEK293 cells belong to the S1P-receptor family; in particular, the data obtained in PC12 cells suggest that the I 1 imidazoline receptors represent a mixture of S1P 1 - and S1P 3 -receptors and/or hetero-dimers of both.

  • Imidazoline binding sites and receptors in cardiovascular tissue.
    General pharmacology, 1999
    Co-Authors: Gerhard J. Molderings, Manfred Göthert
    Abstract:

    Abstract 1. Imidazoline binding sites and receptors and their endogenous ligands have been identified in cardiovascular tissue of various species including human beings. 2. I2- (but only exceptionally I1-)imidazoline binding sites have been shown to exist on cardiac myocytes and vascular smooth muscle cells; at present, their functional role is unknown. 3. The sympathetic nerves supplying the cardiovascular system are endowed with presynaptic inhibitory imidazoline receptors that may become of therapeutic relevance as targets of drugs. 4. ATP-sensitive K+ channels present in heart and blood vessels can be blocked by several Imidazolines and guanidines; hence, those drugs can interfere with the cardioprotective effects resulting from KATP channel activation by a decrease in the endogenous ligand ATP or by drugs. 5. Imidazoline derivatives exhibit antiarrhythmic properties that are due to a reduction of sympathetic tone by central and peripheral mechanisms and to blockade of postsynaptic α2-adrenoceptors in the heart and coronary arteries. 6. Agmatine and clonidine-displacing substance, which are endogenous ligands at imidazoline and α2-receptors, are present in the blood serum and appear to participate in vascular smooth muscle proliferation and blood pressure regulation.

  • Effects of Imidazolines in noradrenaline release in brain: An investigation into their relationship to imidazoline, α2 and H3 receptors
    Neurochemistry international, 1997
    Co-Authors: Eberhard Schlicker, Gerhard J. Molderings, Klaus Fink, M. Kathmann, Manfred Göthert
    Abstract:

    The present study was carried out to clarify whether the Imidazolines clonidine, moxonidine and cirazoline as well as the guanidine aganodine inhibit noradrenaline release in the rat and rabbit brain via imidazoline receptors, α2-adrenoceptors and/or histamine H3 receptors. Slices or synaptosomes from the rat or the rabbit brain were incubated with 3H-noradrenaline and exposed to phenoxybenzamine, which irreversibly blocks presynaptic α2-adrenoceptors and, at considerably lower potency, imidazoline receptors. Tritium overflow in the superfused preparations was evoked electrically (3 Hz; slices) or by K+ 15 mmol/1 (synaptosomes). Noradrenaline and rauwolscine, which possess low affinity, if any, for imidazoline receptors, were used as reference drugs. The evoked overflow in rat brain cortex slices and synaptosomes and in rat medulla oblangata slices, not exposed to phenoxybenzamine, was inhibited by clonidine, moxonidine and noradrenaline. Phenoxybenzamine markedly attenuated the effect of each drug to about the same extent. In rabbit brain cortex slices, not exposed to phenoxybenzamine, the evoked overflow was inhibited by clonidine, aganodine and noradrenaline, facilitated by BDF 6143 (4-chloro-2-(2-imidazoline-2-yl-amino)-isoindoline), idazoxan and rauwolscine and not affected by cirazoline. In slices exposed to phenoxybenzamine, the inhibitory effects of the Imidazolines, of aganodine and of noradrenaline were again attenuated by about the same high degree, the facilitatory effects of BDF 6143, idazoxan and rauwolscine were abolished and cirazoline produced a slight inhibition of the evoked overflow. The latter effect was not affected by high concentrations of rauwolscine and idazoxan (at which these drugs act antagonistic at imidazoline receptors in other models). The specific binding of 3H-Nα-methylhistamine to H3 receptors in rat brain cortex membranes was displaced only by high concentrations of moxonidine (pKi=6.16) and at even lower affinity by aganodine, BDF 6143, cirazoline, clonidine and idazoxan (pKi

  • [^3H]Idazoxan binding to bovine adrenal medullary membranes: identification and pharmacological characterization of I^2-imidazoline sites
    Naunyn-Schmiedeberg's Archives of Pharmacology, 1994
    Co-Authors: Gerhard J. Molderings, Liane Kundt, Manfred Göthert
    Abstract:

    Bovine adrenal chromaffin cells, which have been shown to lack α_2-adrenoceptors, were used to investigate the pharmacological characteristics of [^3H]idazoxan binding sites. The binding of [^3H]idazoxan was very rapid, reversible, partly specific (as defined by cirazoline 0.1 mmol/l; 50% specific binding at [^3H]idazoxan 10 nmol/l), saturable and of high affinity (K_D 13 nmol/l) and, hence, was compatible with the criteria for the identification of an imidazoline binding site (IBS). Since in competition experiments rauwolscine and (−)-adrenaline showed only negligible affinity for these adrenal medullary binding sites, the lack of α_2-adrenoceptors was confirmed. Histamine and amiloride also did not inhibit [^3H]idazoxan binding or caused only negligible inhibitor. In contrast, the specific binding of [^3H]idazoxan was concentration-dependently inhibited by several Imidazolines and guanidines with the following rank order of potency which conforms to the characteristics of the previously defined I_2-IBS (in parentheses: K_i, nmol/l): idazoxan (4) = cirazoline (4) ≫ clonidine (272) = BDF 6143 (299; 4-chloro-2-(2-imidazoline-2-ylamino) isoindoline) > BDF 6100 (563; 2-(2-imidazolin-2-ylamino)-isoindoline) ≥ BDF 7579 (868; (4-chloro-2-isoindolinyl)guanidine) > phentolamine (1424) = naphazoline (1451). Equilibrium [^3H]idazoxan binding was reduced by K^+ but not by Na^+ or the non-hydrolysable GTP-analogue Gpp(NH)p (5′-guanylylimidodiphos-phate; 100 μmol/l). In conclusion, membranes of the bovine adrenal medulla are endowed with non-adrenergic high-affinity [^3H]idazoxan sites which exhibit the pharmacological properties of the amiloride-insensitive subtype of I_2-IBS and probably are not coupled to a G-protein.

  • Pharmacological characterization of the imidazoline receptor which mediates inhibition of noradrenaline release in the rabbit pulmonary artery
    Naunyn-Schmiedeberg's Archives of Pharmacology, 1991
    Co-Authors: Gerhard J. Molderings, F. Hentrich, Manfred Göthert
    Abstract:

    Imidazoline receptors involved in modulation of noradrenaline release were characterized in the rabbit pulmonary artery preincubated with [^3H]noradrenaline and superfused with physiological salt solution containing cocaine, corticosterone and propranolol. Tritium overflow was evoked by transmural electrical stimulation. The α_2-adrenoceptor blocking Imidazolines tolazoline, BDF 6100 [2-(2-imidazoline-2-ylamino)-isoindoline] and BDF 7572 (4,7-dichloro-derivative of BDF 6100) increased the electrically evoked ^3H overflow; the concentration-response curves were bell-shaped. In contrast, two other Imidazolines, i. e. moxonidine and clonidine, two guanidine derivatives structurally related to BDF 6100, i. e. aganodine and BDF 7579 [4-chloro(2-isoindolinel)-guanidine], as well as the catecholamine noradrenaline concentration-dependently inhibited the evoked ^3H overflow. The concentration-response curves for moxonidine, clonidine, aganodine, BDF 7579 and noradrenaline were shifted to the right by rauwolscine. The apparent pA_2 value of rauwolscine against moxonidine was 8.22, whereas those against clonidine, aganodine, BDF 7579 and noradrenaline were in the range of 6.37–6.77 and, hence, considerably lower than reported for α_2-adrenoceptors. In the presence of rauwolscine an inhibitory effect was also observed with the α_2-adrenoceptor blocking Imidazolines tolazoline, BDF 6100, BDF 7572, and the ImidazolinesT 587 [2-(2-chloro-5-trifluoromethylphenylimino)-imidazoline]; the rank order of potency of all guanidines and Imidazolines investigated was: aganodine > BDF 7579 > BDF 7572 > BDF 6100 > clonidine > ST 587 > moxonidine > tolazoline. Amiloride, 1-benzylimidazole and histamine were ineffective. After irreversible blockade of α-adrenoceptors by preexposure to phenoxybenzamine, evoked ^3H overflow was still inhibited by aganodine, BDF 7579 and noradrenaline. Under this condition the maximal effects obtainable with the guanidines and in particular with noradrenaline were lower than in the presence of rauwolscine. These findings are compatible with our previous suggestion that imidazoline receptors mediating inhibition of noradrenaline release exist on the sympathetic nerve terminals of the rabbit pulmonary artery. Comparison of the present data with those obtained in other preparations containing imidazoline recognition sites revealed that those sites are different from the present ones. It is conceivable that the receptor characterized here represents an allosteric site of the α_2-adrenoceptor or a so far undescribed α-adrenoceptor subtype since it can be activated not only by Imidazolines and guanidines but also by noradrenaline and can be blocked by rauwolscine. Comparison of the properties of isoindolines substituted with either aminoimidazoline or guanidine reveals that the Imidazolines (e.g. BDF 7572) possess both α_2-adrenoceptor antagonistic and imidazoline receptor agonistic properties, whereas the analogous guanidines (e. g. aganodine) are imidazoline receptor agonists as well as α_2-adrenoceptor agonists.

Gerhard J. Molderings - One of the best experts on this subject based on the ideXlab platform.

  • s1p receptors in pc12 and transfected hek293 cells molecular targets of hypotensive imidazoline i1 receptor ligands
    Neurochemistry International, 2007
    Co-Authors: Gerhard J. Molderings, Christiana Wolf, Ivar Von Kügelgen, Heinz Bönisch, Michael Brüss, Manfred Göthert
    Abstract:

    Abstract The present study aimed at elucidating the molecular identity of the proposed “I 1 -imidazoline receptors”, i.e. non-adrenoceptor recognition sites via which the centrally acting Imidazolines clonidine and moxonidine mediate a major part of their effects. In radioligand binding experiments with [ 3 H]clonidine and [ 3 H]lysophosphatidic acid on intact, α 2 -adrenoceptor-deficient PC12 cells, moxonidine, clonidine, lysophosphatidic acid and sphingosine-1-phosphate (S1P) competed for the specific binding sites of both radioligands with similar affinities. RNA interference with the rat S1P 1 -, S1P 2 - or S1P 3 -receptor abolished specific [ 3 H]lysophosphatidic acid binding. [ 3 H]Clonidine binding was markedly decreased by siRNA targeting S1P 1 - and S1P 3 -receptors but not by siRNA against S1P 2 -receptors. Finally, in HEK293 cells transiently expressing human S1P 3 -receptors, sphingosine-1-phosphate, clonidine and moxonidine induced increases in intracellular calcium concentration, moxonidine being more potent than clonidine; this is in agreement with the known properties of the “I 1 -imidazoline receptors”. The present results indicate that the “I 1 -imidazoline receptors” mediating effects of clonidine and moxonidine in PC12 and the transfected HEK293 cells belong to the S1P-receptor family; in particular, the data obtained in PC12 cells suggest that the I 1 imidazoline receptors represent a mixture of S1P 1 - and S1P 3 -receptors and/or hetero-dimers of both.

  • Imidazoline binding sites and receptors in cardiovascular tissue.
    General pharmacology, 1999
    Co-Authors: Gerhard J. Molderings, Manfred Göthert
    Abstract:

    Abstract 1. Imidazoline binding sites and receptors and their endogenous ligands have been identified in cardiovascular tissue of various species including human beings. 2. I2- (but only exceptionally I1-)imidazoline binding sites have been shown to exist on cardiac myocytes and vascular smooth muscle cells; at present, their functional role is unknown. 3. The sympathetic nerves supplying the cardiovascular system are endowed with presynaptic inhibitory imidazoline receptors that may become of therapeutic relevance as targets of drugs. 4. ATP-sensitive K+ channels present in heart and blood vessels can be blocked by several Imidazolines and guanidines; hence, those drugs can interfere with the cardioprotective effects resulting from KATP channel activation by a decrease in the endogenous ligand ATP or by drugs. 5. Imidazoline derivatives exhibit antiarrhythmic properties that are due to a reduction of sympathetic tone by central and peripheral mechanisms and to blockade of postsynaptic α2-adrenoceptors in the heart and coronary arteries. 6. Agmatine and clonidine-displacing substance, which are endogenous ligands at imidazoline and α2-receptors, are present in the blood serum and appear to participate in vascular smooth muscle proliferation and blood pressure regulation.

  • Effects of Imidazolines in noradrenaline release in brain: An investigation into their relationship to imidazoline, α2 and H3 receptors
    Neurochemistry international, 1997
    Co-Authors: Eberhard Schlicker, Gerhard J. Molderings, Klaus Fink, M. Kathmann, Manfred Göthert
    Abstract:

    The present study was carried out to clarify whether the Imidazolines clonidine, moxonidine and cirazoline as well as the guanidine aganodine inhibit noradrenaline release in the rat and rabbit brain via imidazoline receptors, α2-adrenoceptors and/or histamine H3 receptors. Slices or synaptosomes from the rat or the rabbit brain were incubated with 3H-noradrenaline and exposed to phenoxybenzamine, which irreversibly blocks presynaptic α2-adrenoceptors and, at considerably lower potency, imidazoline receptors. Tritium overflow in the superfused preparations was evoked electrically (3 Hz; slices) or by K+ 15 mmol/1 (synaptosomes). Noradrenaline and rauwolscine, which possess low affinity, if any, for imidazoline receptors, were used as reference drugs. The evoked overflow in rat brain cortex slices and synaptosomes and in rat medulla oblangata slices, not exposed to phenoxybenzamine, was inhibited by clonidine, moxonidine and noradrenaline. Phenoxybenzamine markedly attenuated the effect of each drug to about the same extent. In rabbit brain cortex slices, not exposed to phenoxybenzamine, the evoked overflow was inhibited by clonidine, aganodine and noradrenaline, facilitated by BDF 6143 (4-chloro-2-(2-imidazoline-2-yl-amino)-isoindoline), idazoxan and rauwolscine and not affected by cirazoline. In slices exposed to phenoxybenzamine, the inhibitory effects of the Imidazolines, of aganodine and of noradrenaline were again attenuated by about the same high degree, the facilitatory effects of BDF 6143, idazoxan and rauwolscine were abolished and cirazoline produced a slight inhibition of the evoked overflow. The latter effect was not affected by high concentrations of rauwolscine and idazoxan (at which these drugs act antagonistic at imidazoline receptors in other models). The specific binding of 3H-Nα-methylhistamine to H3 receptors in rat brain cortex membranes was displaced only by high concentrations of moxonidine (pKi=6.16) and at even lower affinity by aganodine, BDF 6143, cirazoline, clonidine and idazoxan (pKi

  • Inhibition of 5-HT_3 receptor function by Imidazolines in mouse neuroblastoma cells: potential involvement of σ_2 binding sites
    Naunyn-Schmiedeberg's Archives of Pharmacology, 1996
    Co-Authors: Gerhard J. Molderings, Heinz Bönisch, K. Schmidt, M. öthert
    Abstract:

    The influence of several Imidazolines and σ-site ligands on cation influx through the 5-HT_3 receptor channel in NIE-115 mouse neuroblastoma cells was studied by measuring the 2-min influx of the organic cation [^14C] guanidinium induced by 1 μM 5-HT (in the presence of 10 μM substance P in all experiments). In addition, we determined specific binding of [^3H]DTG (1,3-di(2-tolyl)-guanidine), a selective σ-site radioligand, and [^3H] GR65630 (3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone), a selective 5-HT_3 receptor antagonist, to membranes prepared from NIE-115 cells. The 5-HT-induced [^14C]guanidinium influx was inhibited by the Imidazolines, ondansetron, antazoline, idazoxan, BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline), cirazoline, naphazoline, clonidine and by the guanidine agmatine, but not by the catecholamine adrenaline. The inhibitory effect of the Imidazolines on cation influx through the 5-HT_3 receptor channel was mimicked by the σ-site ligands, (±)-ifenprodil, (+)-3-PPP ((R)-3-(3-hydroxyphenyl)-N-propylpiperidine), DTG (1,3-di-tolyl-guanidine), haloperidol, dizocilpine, and ketamine as well as by the polyamines, arcane and spermidine. — Ondansetron inhibited [^3H]GR65630 binding with high affinity, whereas inhibition of binding of this radioligand to the 5-HT_3 receptor by antazoline, BDF 6143, idazoxan, cirazoline, (±)-ifenprodil, (+)-3-PPP, DTG and haloperidol occurred in the high micromolar range. In the competition experiments with [^3H]DTG, (±)-ifenprodil, haloperidol, unlabelled DTG, BDF 6143 and (+)-3-PPP inhibited binding of the radioligand at moderate affinity (K_i values in the range of 1 μM or lower), whereas ondansetron, amazoline, idazoxan, cirazoline, naphazoline, clonidine, tolazoline, efaroxan, RX821002 (2-[2-(2-methoxy-1,4-benzodioxanyl)]imidazoline), ketamine and spermidine exhibited affinity in the high micromolar or millimolar range only. Comparison of the potencies of the ligands (pIC_50% values) in inhibiting 5-HT-induced [^14C]guanidinium influx with their affinities (pK_i values) at the 5-HT recognition sites of the 5-HT_3 receptor and at the σ_2-sites of the N1E-115 cells by means of multiple regression analysis revealed a significant correlation with the affinities at both sites. In conclusion, our data suggest that Imidazolines and σ-ligands, which as a rule possess low affinity for the 5-HT recognition site of the 5-HT_3 receptor, may be assumed to exert their inhibitory effect on cation influx through the 5-HT_3 receptor channels, at least in part, by interacting with σ_2-binding sites.

  • [^3H]Idazoxan binding to bovine adrenal medullary membranes: identification and pharmacological characterization of I^2-imidazoline sites
    Naunyn-Schmiedeberg's Archives of Pharmacology, 1994
    Co-Authors: Gerhard J. Molderings, Liane Kundt, Manfred Göthert
    Abstract:

    Bovine adrenal chromaffin cells, which have been shown to lack α_2-adrenoceptors, were used to investigate the pharmacological characteristics of [^3H]idazoxan binding sites. The binding of [^3H]idazoxan was very rapid, reversible, partly specific (as defined by cirazoline 0.1 mmol/l; 50% specific binding at [^3H]idazoxan 10 nmol/l), saturable and of high affinity (K_D 13 nmol/l) and, hence, was compatible with the criteria for the identification of an imidazoline binding site (IBS). Since in competition experiments rauwolscine and (−)-adrenaline showed only negligible affinity for these adrenal medullary binding sites, the lack of α_2-adrenoceptors was confirmed. Histamine and amiloride also did not inhibit [^3H]idazoxan binding or caused only negligible inhibitor. In contrast, the specific binding of [^3H]idazoxan was concentration-dependently inhibited by several Imidazolines and guanidines with the following rank order of potency which conforms to the characteristics of the previously defined I_2-IBS (in parentheses: K_i, nmol/l): idazoxan (4) = cirazoline (4) ≫ clonidine (272) = BDF 6143 (299; 4-chloro-2-(2-imidazoline-2-ylamino) isoindoline) > BDF 6100 (563; 2-(2-imidazolin-2-ylamino)-isoindoline) ≥ BDF 7579 (868; (4-chloro-2-isoindolinyl)guanidine) > phentolamine (1424) = naphazoline (1451). Equilibrium [^3H]idazoxan binding was reduced by K^+ but not by Na^+ or the non-hydrolysable GTP-analogue Gpp(NH)p (5′-guanylylimidodiphos-phate; 100 μmol/l). In conclusion, membranes of the bovine adrenal medulla are endowed with non-adrenergic high-affinity [^3H]idazoxan sites which exhibit the pharmacological properties of the amiloride-insensitive subtype of I_2-IBS and probably are not coupled to a G-protein.

Shaikh A Ali - One of the best experts on this subject based on the ideXlab platform.

Alan L. Hudson - One of the best experts on this subject based on the ideXlab platform.

  • New imidazoline/α2-adrenoceptors affecting compounds—4(5)-(2-aminoethyl)imidazoline (dihydrohistamine) derivatives. Synthesis and receptor affinity studies
    Bioorganic & Medicinal Chemistry, 2010
    Co-Authors: Adam P. Treder, Włodzimierz Zgoda, Aleksandra Walkowiak, Celeste Ford, Ryszard Andruszkiewicz, Alan L. Hudson
    Abstract:

    Compilation of agmatine structure and imidazoline moiety leads to a new group of imidazoline/α 2 -adrenoceptor ligands, 4(5)-(2-aminoethyl)imidazoline derivatives. In this study the exploration of previously unknown 4(5)-(2-aminoethyl)Imidazolines including the analogues of reported imidazoline and α 2 -aderenoceptors ligands: clonidine, rilmenidine, idazoxan, efaroxan, antazoline, tracizoline is described. The synthesis of a variety of novel 4(5)-(2-aminoethyl)Imidazolines and their I 1 , I 2 , α 2 -adrenoceptors affinities are reported.

  • Inhibition of amine oxidase activity by derivatives that recognize imidazoline I2 sites.
    Journal of Pharmacology and Experimental Therapeutics, 1995
    Co-Authors: Christian Carpéné, Pauline Collon, A. Remaury, Alex Cordi, D Nutt, Alan L. Hudson, Max Lafontan
    Abstract:

    Nonadrenergic imidazoline binding sites (imidazoline I2 sites) have been described to be colocated with monoamine oxidase (MAO) in the mitochondrial fraction of various cell types. In the present work, the authors considered whether this colocation could be associated with a functional interplay. In rat liver membranes, [3H]-idazoxan binding to I2 receptors was competed for by naphazoline and idazoxan, which also shared a high affinity for alpha-2 adrenoceptors (alpha-2 ARs). The chemicals 2-n-heptylimidazoline (S 15430), 1-methyl-5-n-heptylimidazole (S 15674), 2-benzofuran-2-yl-imidazoline (RX 801077) and 2-(1,3-benzodioxanyl)-2-imidazoline (RX 821029) exhibited higher affinity for I2 receptors than for alpha-2 ARs. The most selective agent was S 15430 with a 150-fold higher affinity for liver I2 receptors than for adipocyte alpha-2 ARs. Moreover, [3H]-idazoxan binding was also competed for by several MAO inhibitors (MAOI) that are not imidazoline or guanidinium derivatives such as tranylcypromine, harmaline, clorgiline and pargyline. Rat liver MAO activity was not only inhibited by MAOIs but also by some imidazoline derivatives: cirazoline, naphazoline, S 15674, RX 801077 and RX 821029. Idazoxan had no effect on MAO activity; it neither inhibited MAO nor prevented the inhibition induced by other Imidazolines or MAOIs. This suggested that the ligand recognition site of I2 receptors was distinct from the MAOI target site. Furthermore, some Imidazolines inhibited the activity of bovine plasma amine oxidase, an enzyme that does not possess the same cofactor as MAO and is insensitive to harmaline or pargyline.(ABSTRACT TRUNCATED AT 250 WORDS)