.alpha.-Adrenoreceptor reagents. 3. Synthesis of some 2-substituted 1,4-benzodioxans as selective presynaptic .alpha.2-adrenoreceptor antagonists

Mr, Stillings; Cb, Chapleo; Rc, Butler; Ja, Davis; Cd, England; Myers, Malcolm; Pl, Myers; Tweddle, N. J.; Ap, Welbourn; Jc, Doxey

doi:10.1021/jm00146a013

Cited by 72 publications

(16 citation statements)

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“…It blocks the action of brimonidine (UK 14, 304) in that tissue, with a pA 2 of 9.4. In rat annococcygeus muscle, an assay for á 1 adrenoceptor activity, it showed much lower affinity and the á 2 /á 1 potency ratio calculated from these studies was in excess of 300 (103,114). All subsequent pharmacological studies with the compound have supported these findings (e.g., 68).…”

Section: Pharmacological Characterizationmentioning

confidence: 83%

“…Two molecules showed particularly good characteristics: 2-ethoxy-idazoxan (2-(2-ethoxy-2,3-dihydrobenzo [1,4]dioxin-2-yl)-4,5-dihydro-1H-imidazole, RX 811059) and 2-methoxy-idazoxan (RX 821002, 2-(2-methoxy-2,3-dihydro-benzo [1,4]dioxin-2-yl)-4,5-dihydro-1H-imidazole, Fig. 1) gave improved potency at á 2 -adrenoceptors and á 2 /á 1 selectivity ratios of > 100 (103,114). Furthermore, RX 821002 retains its pharmacological selectivity after tritiation and makes an excellent radioligand for use in receptor binding studies, autoradiography and PET (3,53,54,56,112).…”

Section: Introductionmentioning

confidence: 99%

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RX 821002 as a Tool for Physiological Investigation of α₂‐Adrenoceptors

Clarke

Harris

2002

CNS Drug Reviews

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RX 821002 is the 2-methoxy congener of idazoxan. In binding and tissue studies it behaves as a selective antagonist of á 2 -adrenoceptors, with at least 5 times greater affinity for these receptors than any other binding site. It does not select between the different types of á 2 -receptor. Although this drug probably has no future as a therapeutic agent, it remains a good probe for physiological activity at á 2 -adrenoceptors in animal experiments. A particularly useful feature of this compound is its lack of binding at I 1 and I 2 imidazoline receptors. However, it has relatively high affinity for 5-HT 1A receptors (at which it acts as an antagonist) and a tendency to behave as an inverse agonist at á 2A -adrenoceptors in some cell culture systems. These potential drawbacks may be overcome by careful design of experiments, and the greater selectivity of RX 821002 renders it much superior to yohimbine or idazoxan as a tool for probing physiological actions at á 2 -receptors. It can be compared favorably with other selective antagonists such as atipamezole.In physiological studies, RX 821002 augments norepinephrine release in the frontal cortex and increases drinking behavior in rat. In rabbit, intrathecal administration of this drug enhances somatic and autonomic motor outflows, showing that tonic adrenergic descending inhibition of withdrawal reflexes and sympathetic pre-ganglionic neurons is strong in this species. The potentiation of reflexes may be considered a pro-nociceptive action. In the same model, RX 821002 antagonizes the inhibitory effects of the ì opioid fentanyl, indicating that exogenous opioids synergize with endogenously released norepinephrine in the spinal cord. Thus, the careful use of RX 821002 has revealed several aspects of the physiological activity of á 2 -adrenoceptors in rabbit spinal cord and rat brain. We recommend that RX 821002 and/or compounds with similar selectivity for á 2 -adrenoceptors (atipamezole, MK-912, RS-79948) should be used in preference to yohimbine or idazoxan in all future studies of this type.

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Section: Pharmacological Characterizationmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

RX 821002 as a Tool for Physiological Investigation of α₂‐Adrenoceptors

Clarke

Harris

2002

CNS Drug Reviews

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“…In the mid-1980s, following extensive structure-activity studies with analogues of idazoxan, it was suggested that three major binding regions exists for this type of compound at the CX2-adrenoceptor (Stillings et al, 1985). These were a planar hydrophobic area that interacts with the benzene ring, a site that binds one or both of the benzodioxan oxygens and an imidazoline binding region.…”

Section: Discussionmentioning

confidence: 99%

RS‐45041‐190: a selective, high‐affinity ligand for I₂ imidazoline receptors

Brown¹,

MacKinnon²,

Redfern³

et al. 1995

British J Pharmacology

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1 RS-45041-190 (4-chloro-2-(imidazolin-2-yl)isoindoline) showed high affinity for 12 imidazoline receptors labelled by [3H]-idazoxan in rat (pKi = 8.66 ± 0.09), rabbit (pKi = 9.37 ± 0.07), dog (pKi = 9.32 ± 0.18) and baboon kidney (pKi = 8.85 ± 0.12), but had very low affinity for a2-adrenoceptors in rat cerebral cortex (pKi = 5.7 ± 0.09).2 RS-45041-190 showed low affinity for other adrenoceptors, dopamine, 5-hydroxytryptamine, and muscarinic receptors and dihydropyridine binding sites (selectivity ratio>1000). 3 RS-45041-190 showed moderate potency for the inhibition of monoamine oxidase A in vitro (pIC50= 6.12), but had much lower potency for monoamine oxidase B (pICs = 4.47), neither of which equated with its affinity for I2 receptors. 4 RS-45041-190 (0.001 to 3 mg kg-', i.v. and 1 ng-50 yg i.c.v.) had only small, transient effects on blood pressure and heart rate in anaesthetized rats. In conscious rats, RS-45041-190 had no effect on body core temperature or tail skin temperature (1 mg kg-', s.c.) or on activity or rotarod performance (10 mg kg-1, i.p.). There were also no effects on barbiturate sleeping time in mice after doses of 1-10 mg kg-, i.p.5 RS-45041-190 (10 and 25 mg kg-', i.p.) significantly increased food consumption in rats for up to 4 h after dosing, but unlike idazoxan (10 mg kg-, i.p.) did not increase water consumption. 6 RS-45041-190 is therefore a selective, high-affinity ligand at I2 imidazoline receptors and its hyperphagic effect may suggest a role for I2 imidazoline receptors in the modulation of appetite. However, in the absence of a selective agonist it is unclear whether this ligand is an agonist or an antagonist at I2 receptors.

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“…If a resistant subtype of binding site does indeed exist, the present study suggests it is not the non-adrenoceptor imidazoline binding site (Michel & Insel, 1989;Lehmann et al, 1989;Bousquet et al, 1989), a site which binds a number of a2-adrenoceptor ligands (most notably idazoxan). RX 821002, the methoxy derivative of idazoxan, (Stillings et al, 1985) has little or no affinity for these sites (Langin et al, 1990a,b;Hudson & Nutt, 1990;Miralles et al, 1993a) and yet a similar proportion of binding sites labelled by this compound are lost following EEDQ treatment as seen with other ligands (Pilc et al, 1989). However, recent evidence suggests that EEDQ may be able to inactivate at least partially 12-imidazoline sites in vivo, probably through an indirect action since in vitro administration has little or no effect on these receptors (Miralles et al, 1993b).…”

Section: Discussionmentioning

confidence: 99%