Central nervous system depressant actions of clonidine and UK‐14,304: partial dissociation of EEG and behavioural effects.

Ashton, Heather; Rawlins,

doi:10.1111/j.1365-2125.1978.tb01614.x

Cited by 29 publications

(14 citation statements)

References 11 publications

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“…2). This supports earlier studies where the sedation caused by clonidine was particularly marked relative to its effects on objective performance (Ashton and Rawlins, 1978;Frith et al, 1985). Clonidine appears to make volunteers 'feel drunk' to a relatively greater extent than temazepam.…”

Section: Discussionsupporting

confidence: 85%

Selective effects of clonidine and temazepam on attention and memory

Tiplady

Bowness²,

Stien

et al. 2005

J Psychopharmacol

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The present study compared the effects of clonidine and temazepam on performance on a range of tasks aiming to assess the role of central noradrenergic mechanisms in cognitive function. Fifteen healthy volunteers (seven male, eight female), aged 18-25 years, took part in a five-period crossover study in which they received placebo, temazepam (15 and 30 mg) and clonidine (150 and 300 microg) by mouth in counterbalanced order in sessions at least 4 days apart. A test battery was administered before treatment and at 45, 90 and 135 min after the dose. Performance on most tests was significantly impaired in a dose-related fashion, and subjective sedation was recorded for both drugs. The greatest impairments with clonidine were on attention in the presence of distractors. Clonidine did not affect the formation of new long-term memories, in contrast to temazepam, but did impair measures of working memory. Subjective effects, especially feelings of drunkenness and abnormality, were particularly marked with clonidine. These results support the suggestion that central noradrenergic function may be involved in preventing distraction, but do not confirm other reports suggesting that some aspects of performance are improved with clonidine.

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Section: Discussionsupporting

confidence: 85%

Selective effects of clonidine and temazepam on attention and memory

Tiplady

Bowness²,

Stien

et al. 2005

J Psychopharmacol

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“…The imidazole derivative, UK-14,304, mimics the central nervous system depressant actions of clonidine (Ashton & Rawlins, 1978). In contrast to the results obtained with clonidine we have found that UK-14,304 causes a full aggregatory response in platelets from all donors tested thus far, over a concentration range typically 3 to 4 fold greater than that characterizing the response to adrenaline.…”

Section: Characterization Of Platelet A-adrenoceptorscontrasting

confidence: 72%

Interaction of Selective Α‐adrenoceptor Agonists and Antagonists With Human and Rabbit Blood Platelets

Grant

Scrutton

1980

British J Pharmacology

109

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The selectivity of α‐adrenoceptors mediating the pro‐aggregatory response of human and rabbit platelets to adrenaline and the conditions required to permit expression of an aggregatory response to partial agonists at these α‐adrenoceptors have been studied. Yohimbine causes effective blockade of the pro‐aggregatory responses whereas indoramin and prazosin are ineffective. The clonidine analogue, UK‐14304, is nearly as effective as adrenaline in inducing an aggregatory response in human platelets and a pro‐aggregatory response in rabbit platelets. Cross‐tachyphylaxis between adrenaline and UK‐14304 has been demonstrated. Clonidine is a weak agonist for the pro‐aggregatory response of rabbit platelets and in some donors for the aggregatory response of human platelets. Methoxamine induces a pro‐aggregatory response in human platelets which is blocked by indoramin or prazosin but not by yohimbine. No such response to methoxamine is observed in rabbit platelets. The divalent cation ionophore, A‐23187, induces an aggregatory response to clonidine (in platelets from a non‐responsive donor), phenylephrine and methoxamine in human platelets and to adrenaline, UK‐14304 and clonidine in rabbit platelets. A secretory response to clonidine is also induced by A‐23187 in human platelets. The adenylate cyclase inhibitor, SQ‐22536, is ineffective in either inducing a response to the α‐agonists or potentiating the effect of A‐23187. The aggregatory responses to adrenaline and UK‐14304 in rabbit platelets and to clonidine in human and rabbit platelets, which can be induced by A‐23187, are blocked by yohimbine but not by prazosin or indoramin. From these studies we conclude that the pro‐aggregatory responses of human and rabbit platelets to adrenaline are mediated primarily by α2‐adrenoceptors. The presence of α1‐adrenoceptors on human platelets is confirmed but these receptors do not appear to be present on rabbit platelets. The conditions required for expression of an aggregatory response to partial agonists at the human and rabbit platelet α‐adrenoceptors implicate an increase in cytosolic Ca2+ concentration as a key event in stimulus‐response coupling but do not indicate such a role for depression of cyclic adenosine‐3′,5′‐monophosphate concentration.

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“…Brimonidine was developed in the 1970s as a clonidine analog intended to lower blood pressure without evoking sedative side effects (Ashton & Rawlins, 1978). However, subsequent pre-clinical studies indicated a sedative action for brimonidine in rat (Buerkle & Yaksh, 1998; Hayes et al, 1986; Van Zwieten, 1988).…”

Section: 6 Brimonidine (Uk14304 Bromoxidine)mentioning

confidence: 99%

Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis

Fairbanks

Stone

Wilcox

2009

Pharmacology & Therapeutics

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Endogenous, descending noradrenergic fibers convey powerful analgesic control over spinal afferent circuitry mediating the rostrad transmission of pain signals. These fibers target alpha 2 adrenergic receptors (α 2 ARs) on both primary afferent terminals and secondary neurons, and their activation mediates substantial inhibitory control over this transmission, rivaling that of opioid receptors which share similar a similar pattern of distribution. The terminals of primary afferent nociceptive neurons and secondary spinal dorsal horn neurons express α 2A AR and α 2C AR subtypes, respectively. Spinal delivery of these agents serves to reduce their side effects, which are mediated largely at supraspinal sites, by concentrating the drugs at the spinal level. Targeting these spinal α 2 ARs with one of five selective therapeutic agonists, clonidine, dexmedetomidine, brimonidine, ST91 and moxonidine, produces significant antinociception that can work in concert with opioid agonists to yield synergistic antinociception. Application of several genetically altered mouse lines had facilitated identification of the primary receptor subtypes that likely mediate the antinociceptive effects of these agents. This review provides first an anatomical description of the localization of the three subtypes in the central nervous system, second a detailed account of the pharmacological history of each of these six primary agonists, and finally a comprehensive report of the specific interactions of other GPCR agonists with each of the six principal α 2 AR agonists featured.

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Central nervous system depressant actions of clonidine and UK‐14,304: partial dissociation of EEG and behavioural effects.

Cited by 29 publications

References 11 publications

Selective effects of clonidine and temazepam on attention and memory

Selective effects of clonidine and temazepam on attention and memory

Interaction of Selective Α‐adrenoceptor Agonists and Antagonists With Human and Rabbit Blood Platelets

Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis

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