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A L Hudson

Publications and source records attributed to A L Hudson.

12 recordsLinked to original sources
PubMed1992

Quantification of in vivo binding of [3H]RX 821002 in rat brain: evaluation as a radioligand for central alpha 2-adrenoceptors.

On the basis of its established in vitro characteristics, [3H]RX 821002 was evaluated in rats as an in vivo radioligand for central alpha 2-adrenoceptors. Estimates for in vivo binding potential, obtained by compartmental analyses of time-radioactivity data, ranged between 1.9 for hypothalamus and 0.2 for cerebellum, with a regional distribution in brain which was similar to that observed in vitro. Selectivity and specificity of the signal were checked by predosing with either the alpha 2-antagonists, idazoxan or yohimbine, the alpha 2-agonist, clonidine, or the alpha 1-antagonist, prazosin. Pretreatment of the rats with the selective neurotoxin, DSP-4, had no significant effect on [3H]RX 821002 binding, suggesting that the majority of labelled sites were situated post-junctionally. The studies indicate that [3H]RX 821002 can be used experimentally as an in vivo marker for central alpha 2-adrenoceptors. The size and rate of expression of the specific signal encourage the development and assessment of [11C]RX 821002 for clinical PET studies.

Adrenergic alpha-Antagonists↗
PubMed1992

Characterization and autoradiographical localization of non-adrenoceptor idazoxan binding sites in the rat brain.

1. In rat whole brain homogenates, saturation analysis revealed that both [3H]-idazoxan and [3H]-RX821002, a selective alpha 2-adrenoceptor ligand, bound with high affinity to an apparent single population of sites. However, the Bmax for [3H]-idazoxan was significantly (P less than 0.01) greater than that for [3H]-RX821002. 2. In competition studies, (-)-adrenaline displaced 3 nM [3H]-idazoxan binding with an affinity consistent with [3H]-idazoxan labelling alpha 2-adrenoceptors. However, this displacement was incomplete since 23.68 +/- 1.11% of specific [3H]-idazoxan binding remained in the presence of an excess concentration (100 microM) of (-)-adrenaline. In contrast, unlabelled idazoxan promoted a complete displacement of [3H]-idazoxan binding with a Hill slope close to unity and an affinity comparable with its KD determined in saturation studies. 3. Displacement of [3H]-idazoxan binding by the alpha 2-adrenoceptor antagonists yohimbine, RX821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline) and RX811059 (2-(2-ethoxy-1,4-benzodioxan-2-yl)-2-imidazoline) was more complex, with Hill slopes considerably less than unity, and best described by a two-site model of interaction comprising a high and low affinity component. The proportion of sites with high affinity for each antagonist was similar (60-80%). 4. The rank order of antagonist potency for the high affinity component in each displacement curve (RX821002 greater than RX811059 greater than yohimbine) is similar to that determined against the binding of [3H]-RX821002 to rat brain, suggesting that these components reflect the inhibition of [3H]-idazoxan binding to alpha 2-adrenoceptors.The remaining component in each displacement curve exhibiting low affinity towards these antagonists is attributable to the displacement of [3H]-idazoxin from a non-adrenoceptor idazoxan binding site (NAIBS) since a comparable amount of [3H]-idazoxan binding was not displaced by an excess concentration of (-)-adrenaline.5. The displacement of [3H]-idazoxan binding by RX801023 (6-fluoro-(2-(1,4-benzodioxan-2-yl)-2-imidazoline) was also best described by a model assuming a two site interaction with 20.07 +/- 3.11% of the sites labelled displaying high affinity for RX801023. The Ki of RX801023 for the remainder of the sites labelled was similar to its Ki versus [3H]-RX821002, indicating that this drug displays improved affinity and NAIBS/z2-adrenoceptor selectivity compared with idazoxan.6. In autoradiographical studies, the distribution of 5 nM [3H]-idazoxan binding to sections of rat whole brain was consistent with that reported from previous studies and resembled the distribution ofM2-adrenoceptors. However, when sections of brain were coincubated with concentrations of alpha2-adrenoceptor agonists or antagonists predicted to saturate alpha2-adrenoceptors, there remained distinct areas of binding corresponding to discrete brain nuclei. This remaining binding was however displaced by unlabelled idazoxan (3 microM) or RX801023 (3 microM) indicative of the labelling of NAIBS.7. Quantitative autoradiography of NAIBS revealed several brain nuclei which contained higher densities of these sites than alpha2-adrenoceptors, notably the area postrema, interpeduncular nucleus,arcuate nucleus, ependyma and pineal gland.

Adrenergic alpha-Antagonists↗
PubMed1988

Quantitative autoradiography of [3H]-MK-801 binding sites in mammalian brain.

1. An in vitro receptor autoradiography procedure is described for visualizing binding sites for the excitatory amino acid antagonist radiolabelled MK-801, in rat and gerbil brain sections. 2. Ten micron sections were labelled by incubation at room temperature for 20 min in 30 nM [3H]-MK-801. This was followed by 2 rinses for 20 s in fresh buffer solution. Specifically bound ligand determined with 100 microM unlabelled MK-801 amounted to 55-60% of total. 3. Phencyclidine, (+/-)-SKF 10047, ketamine and 2-aminophosphonovaleric acid (APV) (all 100 microM) prevented the specific binding of [3H]-MK-801. L-Glutamate and N-methyl D-aspartate (NMDA) (100 microM) had no effect. However, L-glutamate prevented the inhibition by APV. 4. The highest concentrations of [3H]-MK-801 binding sites occurred in the hippocampal formation, cerebral cortex, olfactory bulb and thalamus. Very low levels were detected in the brain stem and cerebellum. 5. The distribution of [3H]-MK-801 binding sites was comparable to that of NMDA sites and phencyclidine sites (labelled with [3H]-TCP) but not with high-affinity sigma sites labelled with [3H]-3-PPP. 6. The density of [3H]-MK-801 binding sites in the gerbil hippocampus was examined 1, 2, 6 and 22 days after unilateral carotid artery occlusion for 10 min. Only at 6 and 22 days was the binding reduced (by 36% and 46% respectively) in the CA1 region whereas a significant neuronal loss was apparent at day 2. In CA2 a decrease in binding was only evident at day 22. 7. These results indicate that binding sites for [3H]-MK-801 can be detected in mammalian brain sections by receptor autoradiography. Their distribution supports an association with the NMDA receptor complex and the loss in the hippocampus after carotid artery occlusion indicates their presence on pyramidal cells is vulnerable to ischaemic insult.

Animals↗
PubMed1987

GABAA and GABAB receptor site distribution in the rat central nervous system.

An autoradiographic procedure has been used to determine the quantitative distributions of gamma-aminobutyric acid (GABAA and GABAB) receptor subtypes in rat brain. Although the concentrations of both receptor binding sites were similar in some brain regions GABAA sites generally outnumbered GABAB sites. The highest concentration of GABAA sites were detected in the frontal cortex, the granule cell layer of the cerebellum, the olfactory bulb and the thalamic medial geniculate. The highest concentration of GABAB sites occurred in the molecular layer of the cerebellum, the interpeduncular nucleus, frontal cortex, anterior olfactory nucleus and thalamic nuclei. In addition the globus pallidus, temporal cortex, lateral posterior thalamus, superior colliculus, pontine nucleus, raphe magnus, spinal trigeminal tract and substantia gelatinosa contained significantly more GABAB sites than GABAA sites. The physiological and pharmacological significance of this heterogeneity has yet to be determined.

Animals↗
PubMed1985

[3H](-)Baclofen: an improved ligand for GABAB sites.

[3H](-)Baclofen, the radiolabelled form of the active isomer of baclofen, has been used as a ligand for GABAB (gamma-aminobutyric acid) receptors on synaptic membranes from whole brain of rat. The pharmacological profile for displacement of this ligand was observed to be identical with that for the racemic ligand [3H](+/-)baclofen and [3H]GABA under conditions where GABAB, but not GABAA sites, were labelled. The displaceable (specific) portion of membrane-bound [3H](-)baclofen was 47.5 +/- 2.3% of the total which was twice that obtained previously with [3H](+/-)baclofen. Two binding components were observed with affinities of 19 and 304 nM and binding capacities of 0.37 and 1.58 pmol/mg protein respectively. It is suggested that [3H](-)baclofen is an improvement over the labelled racemic form and binds to the same sites. It should provide a more reliable tool for studying GABAB receptors.

Animals↗
PubMed1979

Synthesis and biological activities of [7-(azetidine-2-carboxylic acid)]-oxytocin and -lysine-vasopressin.

[7-(Azetidine-2-carboxylic acid)]-oxytocin and -lysine-vasopressin have been synthesised by a (6 + 3) strategy using protected hexapeptide acids with preformed disulphide bridges, and their biological activities have been investigated. All activities were reduced but not to the same extent. In assays of pressor and antidiuretic activity it was observed consistently that the responses to the vasopressin analogue were of shorter duration than responses to lysine-vasopressin of the same amplitude.

Amino Acid Sequence↗
PubMed1978

Isoguvacine, isonipecotic acid, muscimol and N-methyl isoguvacine on the GABA receptor in rat sympathetic ganglia.

The GABA-mimetic activities of 4 analogues muscimol, isonipecotic acid, isoguvacine and N-methyl isoguvacine have been examined at the GABA receptor in the rat isolated superior cervical ganglion. The depolarizing action of all 4 analogues could be selectively antagonized by bicuculline methochloride and isopropyl bicyclophosphate. Muscimol was the only analogue more potent than GABA (molar potency ratio = 5.08 +/- 0.707). The potency of isoguvacine was 0.23 +/- 0.026 and isonipecotic acid 0.011 +/- 0.0028. N-methyl isoguvacine was less than 0.001 GABA.

Animals↗