Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Andrew Sleight is active.

Publication


Featured researches published by Andrew Sleight.


Neuropharmacology | 2004

5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation—an effect sensitive to NMDA receptor antagonism

Madeleine V. King; Andrew Sleight; Marie Woolley; Ian A. Topham; Charles A. Marsden; Kevin C.F. Fone

5-HT(6) receptors are expressed in brain regions associated with learning and memory, and blockade of their function increases central cholinergic and glutamatergic neurotransmission and enhances cognitive processes. This study examined the effects of acute systemic administration of two selective 5-HT(6) receptor antagonists Ro 04-6790 and SB-271046 (10 mg kg(-1) i.p.) on acquisition, consolidation, and retrieval in the novel object discrimination (NOD) task, a two-trial test of recognition memory in which rats exposed to two identical objects during a familiarisation trial can discriminate a novel from a familiar object during the subsequent choice trial, following inter-trial delays of up to 3 h. 5-HT(6) receptor antagonist administration 20 min prior to or immediately after the familiarisation trial, but not 20 min prior to the choice trial reversed the deficit in object discrimination produced by a 4 h inter-trial interval. The nootropic effects of the 5-HT(6) receptor antagonists in this task thus appear to involve enhanced consolidation. Pre-treatment with the non-competitive NMDA receptor antagonist MK-801 (0.05 mg kg(-1) i.p.) prevented the effect of Ro 04-6790 on delay-induced deficits in object discrimination. This suggests that the 5-HT(6) receptor antagonist-induced enhancement of consolidation involves increased central glutamatergic neurotransmission.


Neuropharmacology | 2001

A role for 5-ht6 receptors in retention of spatial learning in the Morris water maze

M.L Woolley; J.C Bentley; Andrew Sleight; Charles A. Marsden; Kevin C.F. Fone

This study investigates the effect of intracerebroventricular administration of a 5-ht6 antisense oligonucleotide (AO) complementary to bases 1-18 of the rat 5-ht6 cDNA initiation sequence (Mol. Pharmacol. 43 (1993) 320) (1.5 microg twice daily for six days) and i.p. injection of a selective 5-ht6 receptor antagonist Ro 04-6790 (10 or 30 mg/kg once daily for three days) on acquisition and retention in the Morris water maze. Neither the 5-ht6 AO (which reduced cortical [3H]-LSD binding sites by 10-16%) nor Ro 04-6790 affected acquisition, but both enhanced retention of the learned platform position such that rats spent significantly longer searching the trained platform position than any other area during the probe tests. Furthermore, neither AO nor Ro 04-6790 had any effect on the time taken to reach a raised visible platform, indicating that visual acuity was unimpaired. In addition, AO reduced both food consumption and body weight and the later effect was also seen following Ro 04-6790, suggesting a role for the 5-ht6 receptor in the regulation of feeding. Hence, while the underlying mechanism remains unclear, enhanced retention of spatial learning following both AO and 5-ht6 antagonist administration strongly indicate a role for this receptor in memory processes.


British Journal of Pharmacology | 1998

Characterization of Ro 04‐6790 and Ro 63‐0563: potent and selective antagonists at human and rat 5‐HT6 receptors

Andrew Sleight; Frank Boess; Michael Bös; Bernard Levet-Trafit; Claus Riemer; Anne Bourson

This study describes the in vitro characterization of two potent and selective 5‐HT6 receptor antagonists at the rat and human recombinant 5‐HT6 receptor. In binding assays with [3H]‐LSD, 4‐amino‐N‐(2,6 bis‐methylamino‐pyrimidin‐4‐yl)‐benzene sulphonamide (Ro 04‐6790) and 4‐amino‐N‐(2,6 bis‐methylamino‐pyridin‐4‐yl)‐benzene sulphonamide (Ro 63‐0563) had mean pKi values ±s.e.mean at the rat 5‐HT6 receptor of 7.35±0.04 and 7.83±0.01, respectively and pKi values at the human 5‐HT6 receptor of 7.26±0.06 and 7.91±0.02, respectively. Both compounds were found to be over 100 fold selective for the 5‐HT6 receptor compared to 23 (Ro 04‐6790) and 69 (Ro 63‐0563) other receptor binding sites. In functional studies, neither compound had any significant effect on basal levels of cyclicAMP accumulation in Hela cells stably expressing the human 5‐HT6 receptor, suggesting that the compounds are neither agonists nor inverse agonists at the 5‐HT6 receptor. However, both Ro 04‐6790 and Ro 63‐0563 behaved as competitive antagonists with mean ±s.e.mean pA2 values of 6.75±0.07 and 7.10±0.09, respectively. In rats habituated to observation cages, Ro 04‐6790 produced a behavioural syndrome similar to that seen following treatment with antisense oligonucleotides designed to reduce the expression of 5‐HT6 receptors. This behavioural syndrome consisted of stretching, yawning and chewing. Ro 04‐6790 and Ro 63‐0563 represent valuable pharmacological tools for the identification of 5‐HT6 receptors in natural tissues and the study of their physiological function.


British Journal of Pharmacology | 1999

Investigation of stretching behaviour induced by the selective 5‐HT6 receptor antagonist, Ro 04–6790, in rats

Jane C Bentley; Anne Bourson; Frank Boess; Kevin C.F. Fone; Charles A. Marsden; Nadine Petit; Andrew Sleight

The present study examined the effects of the selective 5‐HT6 receptor antagonist 4‐amino‐N‐(2, 6 bis‐methylamino‐pyrimidin‐4‐yl)‐benzene sulphonamide (Ro 04–6790) on locomotor activity and unconditioned behaviour in male Sprague Dawley rats (230–300 g). In non‐quantified behavioural observations, animals treated with Ro 04–6790 (3, 10 or 30 mg kg−1, i.p) showed no overt behavioural signs except a dose‐dependent reduction in locomotor activity and a behavioural syndrome of stretching, yawning and chewing. The latter behaviour was most pronounced between 30 and 90 min following the administration of Ro 04–6790. Detailed analysis of the stretching and yawning behaviour showed that Ro 04–6790 (3, 10 or 30 mg kg−1, i.p.) dose‐dependently induced stretching. The number of stretches observed following treatment with either Ro 04–6790 (10 mg kg−1 i.p.) or Ro‐04‐6790 (30 mg kg−1, i.p.) was significantly greater than that observed in saline‐treated rats. The yawning behaviour, however, was not dose‐dependent nor was the number of yawns in any of the drug treated groups significantly greater than in those treated with saline. Pretreatment (30 min) with the non‐selective muscarinic antagonists scopolamine (0.1, 0.3 or 1 mg kg−1, i.p.) and atropine (0.3, 1 or 3 mg kg−1, s.c.) but not methylatropine (1, 3 or 10 mg kg−1, s.c) significantly inhibited stretching induced by Ro 04–6790 (30 mg kg−1, i.p.). The dopamine D2‐like receptor antagonist, haloperidol (0.03, 0.1 or 0.3 mg kg−1, s.c.) given at the same time as Ro 04–6790 (30 mg kg−1, i.p.) had no effect on the stretching induced by the 5‐HT6 antagonist. These data suggest that systemic injection of the 5‐HT6 antagonist, Ro 04–6790, produces a stretching behaviour that appears to be mediated by an increase in cholinergic neurotransmission in the CNS and which could be a useful functional correlate for 5‐HT6 receptor blockade. There is no evidence for dopamine D2‐like receptor involvement in this behaviour.


Neuropharmacology | 1997

Functional and Radioligand Binding Characterization of Rat 5-HT6 Receptors Stably Expressed in HEK293 Cells

Frank Boess; Frederick J. Monsma; C. Carolo; V. Meyer; Alain Rudler; Catherine Zwingelstein; Andrew Sleight

We have stably expressed the rat 5-HT6 receptor in HEK293 cells at a density of > 2 pmol/mg protein, as determined in equilibrium binding studies with [3H]-LSD and [3H]-5-HT and compared the affinity of a range of compounds in competition binding experiments with either [3H]-LSD or [3H]-5-HT as radioligand. A variety of tryptamine derivatives were tested and showed a significantly higher affinity when the 5-HT6 receptor was labelled with [3H]-5-HT, whereas ergoline compounds and several antagonists had higher affinities when [3H]-LSD was used as radioligand. Subsequently we examined the ability of LSD, 5-HT and a number of tryptamine derivatives to stimulate cAMP accumulation in order to determine their agonist potency and efficacy. We observed the following rank order of potency: LSD > omega-N-methyl-5-HT approximately bufotenine approximately 5- methoxytryptamine > 5-HT > 2-methyl-5-HT approximately 5-benzyloxytryptamine approximately tryptamine > 5-carboxamidotryptamine > > 5-HTQ. LSD, lisuride, 2-methyl-5-HT, tryptamine and 5-benzyloxytryptamine behaved as partial agonists relative to 5-HT. The rank order of potency of the tryptamine compounds correlated well with their affinities determined in binding assays. In addition, we have tested a number of antagonists in this system (rank order of potency: methiothepin, clozapine, mianserin and ritanserin). This characterization of the pharmacological properties of recombinant 5-HT6 receptor will facilitate the identification of 5-HT6 receptor-mediated responses in physiological systems.


Neuropharmacology | 1995

Effects of the 5-HT1D receptor antagonist GR127935 on extracellular levels of 5-HT in the guinea-pig frontal cortex as measured by microdialysis

M. Skingle; Andrew Sleight; W. Feniuk

The involvement of 5-HT1D receptors in the regulation of 5-HT release in the guinea-pig brain was examined using the novel 5-HT1D receptor blocking drug GR127935. Levels of 5-HT were measured in frontal cortex of anaesthetized guinea-pigs using microdialysis. The infusion of GR127935 (100 nM) through the dialysis probe into frontal cortex caused a significant increase (61 +/- 8%) in cortical extracellular levels of 5-HT. The increase was transient (approximately 40 min) even in the continuous presence of GR127935. The transient increase was abolished by tetrodotoxin (1 microM). The 5-HT1 receptor agonist GR46611 (10 mg/kg s.c.) caused a significant and sustained (> 100 min) reduction in extracellular levels of 5-HT (65 +/- 5%). This response was abolished in animals pre-treated with GR127935, 0.05 mg/kg i.p. Paradoxically, systemic administration of higher doses of GR127935 (0.1-1 mg/kg i.p.) in naive anaesthetized guinea-pigs caused significant and sustained (> 120 min) decreases (> 65%) in cortical levels of 5-HT. The increase in extracellular 5-HT seen following infusion of GR127935 into frontal cortex may be due to GR127935 blocking 5-HT terminal autoreceptors causing a subsequent increase in the outflow of 5-HT from pre-synaptic terminals. This conclusion is supported by the ability of GR127935 to block the decrease in 5-HT induced by the 5-HT1 receptor agonist GR46611.(ABSTRACT TRUNCATED AT 250 WORDS)


British Journal of Pharmacology | 2009

Characterization of (R,S)‐5,7‐di‐tert‐butyl‐3‐hydroxy‐3‐trifluoromethyl‐3H‐benzofuran‐2‐one as a positive allosteric modulator of GABAB receptors

Pari Malherbe; R. Masciadri; R. D. Norcross; Frédéric Knoflach; C. Kratzeisen; M.-T. Zenner; Y. Kolb; A. Marcuz; J. Huwyler; T. Nakagawa; Richard Hugh Philip Porter; Andrew William Thomas; Joseph G. Wettstein; Andrew Sleight; Will Spooren; Eric Prinssen

As baclofen is active in patients with anxiety disorders, GABAB receptors have been implicated in the modulation of anxiety. To avoid the side effects of baclofen, allosteric enhancers of GABAB receptors have been studied to provide an alternative therapeutic avenue for modulation of GABAB receptors. The aim of this study was to characterize derivatives of (R,S)‐5,7‐di‐tert‐butyl‐3‐hydroxy‐3‐trifluoromethyl‐3H‐benzofuran‐2‐one (rac‐BHFF) as enhancers of GABAB receptors.


Behavioural Brain Research | 1995

Effects of altered 5-ht6 expression in the rat: functional studies using antisense oligonucleotides

Andrew Sleight; Frederick J. Monsma; E. Borroni; R.H. Austin; Anne Bourson

The purpose of the present study was to determine whether the 5-ht6 receptor is functionally expressed in the rat brain by blocking its translation from mRNA with treatments of phosphorothioate antisense oligonucleotides. Rats were treated with either saline, antisense (AO) or scrambled oligonucleotides (SO) for 4 days. Treatment with AO reduced the number of [3H]LSD binding sites in the frontal lobes by 30% but had no significant effect on the number of 5-HT1A and 5-HT2A receptor binding sites in the cortex of the rats. A behavioural syndrome of yawning, stretching and chewing, however, was observed in AO treated rats but not in any of the other treatment groups. This AO-specific behaviour had returned to normal 5 days after cessation of the oligodeoxynucleotide treatment. These data suggest that the 5-ht6 receptor has a physiological function in the rat brain where it appears to be under the tonic control of endogenous 5-HT.


European Journal of Medicinal Chemistry | 2001

5-HT6 receptor antagonists: lead optimisation and biological evaluation of N-aryl and N-heteroaryl 4-amino-benzene sulfonamides

Michael Bös; Andrew Sleight; Thierry Godel; James R. Martin; Claus Riemer; Heinz Stadler

RO-04-6790 (6a) has been identified in a random screen for 5-HT(6) receptor antagonists. In a medicinal chemistry optimisation program a series of analogs comprising N-heteroaryl- and N-arylbenzenesulfonamides have been synthesised and investigated for their binding affinity. Compounds with a logD profile indicative of brain penetration have been subjected to in vivo testing for reversal of a scopolamine-induced retention deficit in a passive avoidance paradigm.


Journal of Neurochemistry | 1985

Inhibition of Monoamine Oxidase Selectively in Brain Monoamine Nerves Using the Bioprecursor (E-β-Fluoromethylene-m-Tyrosine (MDL 72394), a Substrate for Aromatic L-Amino Acid Decarboxylase

Michael G. Palfreyman; Ian A. McDonald; John R. Fozard; Yves Mély; Andrew Sleight; Monique Zreika; Joseph Wagner; Philippe Bey; Peter J. Lewis

Abstract: (E)‐β‐Fluoromethylene‐m‐tyrosine (FMMT) is a dual‐enzyme‐activated inhibitor of monoamine oxidase (MAO). The compound is not an inhibitor per se but is decarboxylated by aromatic L‐amino acid decarboxylase (AADC) to yield a potent enzyme‐activated irreversible inhibitor of MAO, (E)‐β‐fluoromethylene‐m‐tyramine, which shows some selectivity for inhibition of MAO type A. Decarboxylation of FMMT was demonstrated in vitro using hog kidney AADC and in vivo in rats by the ability of α‐monofluoromethyldopa (MFMD), a potent inhibitor of AADC, to prevent MAO inhibition produced by FMMT. In isolated synaptosomes. FMMT was decarboxylated by AADC, and, furthermore, the compound was actively transported into these isolated nerve endings. An active transport into the CNS has also been demonstrated in vivo by performing competition experiments with leucine. To demonstrate that FMMT is preferentially decarboxylated within monoamine nerves of the CNS, the nigrostriatal 3,4‐dihydroxyphenylethylamine (dopamine) pathway of rats was unilaterally lesioned with 6‐hydroxydopamine or infused with MFMD. Under these conditions, MAO inhibition produced by orally administered FMMT in the striatum ipsilateral to the lesion or infusion was markedly attenuated. Combination of FMMT with an inhibitor of extracerebral AADC, such as carbidopa, protected peripheral organs against the MAO inhibitory effects and concomitantly enhanced MAO inhibition in the CNS. Such combinations had a greatly reduced propensity to augment the cardiovascular effects of intraduodenally administered tyramine, when compared with FMMT given alone or with clorgyline, a selective inhibitor of MAO type A. The results obtained with FMMT suggest the possibility of achieving selective inhibition of MAO within monoamine nerves of the CNS and, further, suggest that combination of FMMT with an inhibitor of extracerebral AADC will reduce the propensity of this inhibitor to produce adverse interactions with tyramine.

Collaboration


Dive into the Andrew Sleight's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge