BACKGROUND AND PURPOSEWe have investigated the distribution of α‐adrenoceptors in sheep internal anal sphincter (IAS), as a model for the human tissue, and evaluated various imidazoline derivatives for potential treatment of faecal incontinence.EXPERIMENTAL APPROACHSaturation and competition binding with 3H‐prazosin and 3H‐RX821002 were used to confirm the presence and density of α‐adrenoceptors in sheep IAS, and the affinity of imidazoline compounds at these receptors. A combination of in vitro receptor autoradiography and immunohistochemistry was used to investigate the regional distribution of binding sites. Contractile activity of imidazoline‐based compounds on sheep IAS was assessed by isometric tension recording.KEY RESULTSSaturation binding confirmed the presence of both α1‐ and α2‐adrenoceptors, and subsequent characterization with sub‐type‐selective agents, identified them as α1A‐ and α2D‐adrenoceptor sub‐types. Autoradiographic studies with 3H‐prazosin showed a positive association of α1‐adrenoceptors with immunohistochemically identified smooth muscle fibres. Anti‐α1‐adrenoceptor immunohistochemistry revealed similar distributions of the receptor in sheep and human IAS. The imidazoline compounds caused concentration‐dependent contractions of the anal sphincter, but the maximum responses were less than those elicited by l‐erythro‐methoxamine, a standard non‐imidazoline α1‐adrenoceptor agonist. Prazosin (selective α1‐adrenoceptor antagonist) significantly reduced the magnitude of contraction to l‐erythro‐methoxamine at the highest concentration used. Both prazosin and RX811059 (a selective α2‐adrenoceptor antagonist) reduced the potency (pEC50) of clonidine.CONCLUSIONS AND IMPLICATIONSThis study shows that both α1‐ and α2‐adrenoceptors are expressed in the sheep IAS, and contribute (perhaps synergistically) to contractions elicited by various imidazoline derivatives. These agents may prove useful in the treatment of faecal incontinence.

01 Sep 2005·European Journal of PharmacologyQ3 · MEDICINE

Effect of BU98008, an imidazoline1-binding site ligand, on body temperature in mice

Q3 · MEDICINE

Article

Author: Robinson, Emma S. J. ; Cambridge, Naomi

Previous studies using the novel imidazoline1-binding site ligand 1-(4,5-dihydro-1H-imidazol-2-yl)isoquinoline hydrochloride, BU98008, have shown it induces a hypothermic response in rodents following intraperitoneal administration. Radioligand binding data has shown that BU98008 is a highly selective imidazoline1-binding site ligand with 300 fold selectively for the imidazoline1-binding site relative to alpha2-adrenoceptors. However, alpha2-adrenoceptor agonists are known to induce hypothermia, therefore, the present study has investigated the ability of the selective alpha2-adrenoceptor antagonist, RX811059 (2-ethoxy idazoxan) and the mixed imidazoline1-binding site/alpha2-adrenoceptor antagonist, efaroxan, to attenuate the BU98008-induced hypothermia. Preliminary experiments confirmed that BU98008 induced a dose-dependent decrease in body temperature in mice at 10 and 20 mg/kg. The response was not affected by pre-treatment with RX811059 but was significantly attenuated following pre-treatment with efaroxan. These data suggest that BU98008-induced hypothermia is mediated by activation of imidazoline1-binding site. Body temperature may therefore provide a novel assay for investigating agonist and antagonist action at the imidazoline1-binding site.

01 Dec 2002·NeuroscienceQ3 · MEDICINE

α2-Adrenoceptor activation increases a cationic conductance and spontaneous GABAergic synaptic activity in dopaminergic neurones of the rat substantia nigra

Q3 · MEDICINE

Article

Author: Guyon, A. ; Cathala, L. ; Eugene, D. ; Paupardin-Tritsch, D.

Noradrenaline (NA) plays an important role in compensating for the loss in dopaminergic (DA) function following lesions of the DA neurones of the substantia nigra (SN). Alpha2-adrenoceptors are largely expressed in these neurones, but the cellular response to their activation is unknown. Whole-cell patch-clamp recordings were made from DA neurones of rat SN. At a holding potential of -60 mV, bath application of NA (50 microM) induced an inward current (-20.3+/-10.0 pA) in 50% of the recorded neurones. This effect was mimicked by UK-14304 (50 microM), a specific alpha2-adrenoceptor agonist, whereas alpha1-adrenoceptor and beta-adrenoceptor agonists failed to induce a response. Surprisingly, alpha2-adrenoceptor antagonists (idazoxan, RX-811059, SKF-86466 and yohimbine) also induced an inward current that could occlude the one induced by UK-14304, suggesting that they may act as alpha2-adrenoceptor agonists. The inward current results from an increase in cationic conductance identical to the one previously described in these neurones, as neurotensin (1 microM), known to activate it, occluded the inward current induced by UK-14304. In addition, GABAergic miniature inhibitory postsynaptic current frequency was increased by activation of presynaptic alpha2-adrenoceptors. We conclude that the effects of NA on alpha2-adrenoceptors can contribute to the previously described composite action of NA on DA neurone firing and can be pharmacologically differentiated from the effect of NA on DA and neighbouring neurones known to be mediated through alpha1-adrenoceptors.

100 Deals associated with Ethoxy-idazoxan

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Indication	Highest Phase	Country/Location	Organization	Date
Poisoning	Phase 1	-	Indivior PLC	-
Poisoning	Phase 1	-	Pierre Fabre SA	-
Poisoning	Phase 1	-	University of Aston	-

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