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Biomedical subjects

H Hall

Publications and source records attributed to H Hall.

At least 163 records · Page 9Linked to original sources
PubMed1986

Comparisons between the in vitro binding of two substituted benzamides and two butyrophenones to dopamine-D2 receptors in the rat striatum.

The in vitro dopamine-D2 receptor binding profiles of two substituted benzamides (3H-sulpride and 3H-raclopride) and two butyrophenones (3H-spiperone and 3H-domperidone) were compared. 3H-Raclopride, 3H-domperidone and 3H-sulpride labelled approximately the same number of binding sites in the rat striatum, while 3H-spiperone labelled a higher number of binding sites. This latter finding was suggested to be due to the labelling of 5-HT2 receptors in addition to the dopamine-D2 binding sites since the labelling of these 5-HT2 receptors with 3H-spiperone could be avoided by the addition of the 5-HT2 receptor antagonist ketanserin. The inhibition constants (Ki) of the unlabelled compounds were similar to the Kd values obtained in the saturation analyses with 3H-raclopride, 3H-domperidone and 3H-sulpiride but were significantly higher when 3H-spiperone was used as radioligand. Addition of ketanserin to 3H-spiperone made the Ki values more similar to those obtained with the other radioligands. The implications of these findings in testing antidopaminergic activity is discussed.

Animals↗
PubMed1985

Specific in vitro and in vivo binding of 3H-raclopride. A potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain.

The substituted benzamide drug raclopride, [((-)-(S)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate; FLA 870(-); A40664] was shown to be a potent and selective antagonist of dopamine D-2 receptors by its high affinity for striatal 3H-spiperone binding sites and low potency to block dopamine stimulated adenylate cyclase in vitro. In vitro studies showed that 3H-raclopride binds with a high affinity (KD = 1.2 nM) and a low proportion of non-specific binding to rat striatal homogenates. The binding of 3H-raclopride is saturable (Bmax = 23.5 pmoles/g wet wt) and reversible (dissociation half-time = 30 min) with a regional distribution of the specifically bound drug showing the following rank-order: striatum greater than nucleus accumbens greater than olfactory tubercle greater than septum greater than hypothalamus greater than hippocampus greater than frontal cortex. After in vivo administration, 3H-raclopride accumulates preferentially in dopamine rich brain areas with approximately 10 times higher levels in the striatum than in the cerebellum, when examined 30 min after injection. The in vivo binding of 3H-raclopride was saturable, reversible and showed a low component of non-specific binding. More than 90% of the drug reached the brain in a non-metabolized form as judged by thin-layer chromatography. Pharmacological analysis of 3H-raclopride binding showed that it could be displaced by dopamine agonists and antagonists but not by serotoninergic or noradrenergic drugs. Taken together, the results suggest that 3H-raclopride labels dopamine D-2 receptors with high specificity in the rat brain both in vitro and in vivo, and thus, that it should be a useful tool in studies of central dopamine D-2 receptors.

Adenylyl Cyclases↗
PubMed1985

A simple, rapid, reliable reverse haemolytic plaque assay and positive quality control test for routine use.

A simple, rapid, reliable protein A reverse haemolytic plaque assay is described. Monolayers of protein A-coupled sheep red blood cells, in liquid medium, are formed in shallow 15 mm diameter chambers of the type commercially available for leucocyte migration inhibition assays. No agarose is necessary and the chambers are quick and easy to use, economical of reagents, and of a constant size and volume. Results compare favourably with those obtained using Cunningham chambers. The assay is ideal for clinical studies in which large numbers of samples are assayed daily. A positive quality control test for the protein A reverse hemolytic plaque assays is described. Spleen cells are stimulated with pokeweed mitogen to give high numbers of secreting cells. The cells are harvested on day 6 of culture and stored in aliquots at -70 degrees C. When thawed and tested in the protein A assay, these secreting cells form a sensitive and reproducible monitor of the day-to-day performance of the assay. Variation between operators and between batches of reagents may also be checked if desired, with little additional time, effort or expense.

Animals↗
PubMed1985

Some in vitro receptor binding properties of [3H]eticlopride, a novel substituted benzamide, selective for dopamine-D2 receptors in the rat brain.

The substituted benzamide compound eticlopride, (S)-(-)-5-chloro-3-ethyl-N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamide hydrochloride (FLB 131), has been shown to selectively block dopamine-D2 binding sites in the rat brain. The compound was tritium-labelled to high specific radioactivity and was used for in vitro receptor binding studies. [3H]Eticlopride was found to bind specifically to rat brain homogenates with the highest binding in the striatum and lowest in the hippocampus. The binding was saturable with a high number of binding sites (49.5 pmol/g) and with very high affinity (0.17 nM). As with other benzamides, the binding of [3H]eticlopride was highly sodium-dependent. Lesioning of the striatal neurons with ibotenic acid reduced the binding by 50% while lesioning of the nigrostriatal pathways with 6-hydroxydopamine was without effect on the observed binding. The binding of [3H]eticlopride was inhibited potently by neuroleptic drugs, while compounds known not to interact with the dopamine-D2 binding sites were inactive. It is concluded that this new dopamine-D2 antagonist may be a useful tool for the study of dopamine-D2 binding sites due to its high affinity and good selectivity.

Animals↗
PubMed1985

The effects of manipulation of presynaptic 5-HT nerve terminals on postsynaptic 5-HT1 and 5-HT2 binding sites of the rat brain.

The effects of long-term treatment of rats with alaproclate and amiflamine on the number and kinetics of 5-HT1 and 5-HT2 binding sites were investigated using in vitro receptor binding techniques. Some other studies have reported down-regulatory effects of alaproclate and amiflamine on 5-HT2 binding sites in certain regions of the rat forebrain, but no such effects could be detected in the present study. Induction of a high-affinity binding site for 3H-5-HT after long-term antidepressant treatment, as has been reported elsewhere, was not obtained in the present study. The results are compared to the effects obtained by treatment of rats with para-chloroamphetamine (PCA), which depletes the presynaptic neurons of monoamines. These different types of treatment do not cause any change in the binding properties of the specific 5-HT binding sites. It is thus concluded that such manipulations of the presynaptic 5-HT neurons do not affect the postsynaptic 5-HT1 and 5-HT2 binding sites.

Alanine↗
PubMed1985

The radiolysis and radioracemization of amino acids on clays.

L-Leucine and its hydrochloride salt have been deposited on the clay minerals kaolin and bentonite, and the amino acid/clay preparations have been irradiated in a 3000 Ci60Co gamma-ray source for radiation dosages that achieved 2-89% radiolysis of the leucine. The undecomposed leucine was thereupon recovered and both percent radiolysis and percent radioracemization were determined. Similar studies were made using solid L-leucine and its hydrochloride, and L-leucine in 0.1 M aqueous solution. It has been found that radiolysis and radio-racemization in these and the previously studied leucine systems follow pseudo-first-order rate laws, and the corresponding specific rate constants are evaluated and compared. Leucine and its hydrochloride salt proved to be the most stable to both radiolysis and radioracemization, followed by leucine and its HCl salt on kaolin, followed by leucine and its HCl salt on bentonite, with leucine (and its HCl and Na salts) in aqueous solution being least stable to both radiolysis and (except for the HCl salt) radioracemization. Implications of these observations as regards the Vester-Ulbricht mechanism for the origin of optical activity are discussed.

Bentonite↗
PubMed1985

Autoradiographic localization of [3H]neurotensin-binding sites in the hippocampal region of the rat and primate brain.

The distribution of binding sites for the neuropeptide neurotensin was studied in the hippocampal region of the rat, monkey and human brain by using the method of in vitro receptor autoradiography. Biochemical studies of [3H]neurotensin binding to homogenates or sections of the rat hippocampal region showed it to be saturable, reversible and of high specificity. Displacement studies showed that neurotensin-(1-13) and neurotensin-(8-13) were active, while neurotensin-(1-6) and (1-8) were inactive in blocking the specific binding of [3H]neurotensin to hippocampal sections. The autoradiographic studies showed a highly heterogeneous pattern of [3H]neurotensin binding in the hippocampal region: the highest density was present in the entorhinal area while little binding was found in the Ammon's horn. In the rat most of the [3H]neurotensin binding was found in layer II of the medial entorhinal area and in the parasubiculum, while the lateral entorhinal area contained fewer [3H]neurotensin-binding sites. The laminar distribution of binding remained the same throughout the longitudinal axis of the entorhinal area. The pattern of [3H]neurotensin binding in the monkey resembled that seen in the rat inasmuch as the medial was rich and the lateral entorhinal area was poor in [3H]neurotensin-binding sites. In the medial entorhinal area most binding was found in layers I-IV. Unlike in the rat, the hilus of the monkey contained moderate and the molecular layer of the area dentata few [3H]neurotensin-binding sites. In the human brain the outer three layers of both the medial and the lateral entorhinal area contained binding sites for [3H]neurotensin. Binding sites for [3H]neurotensin were found also in the parasubiculum and in the molecular layer of the area dentata of the human brain. The present autoradiographic studies show that the hippocampal region of the rat and primate brain is rich in binding sites for [3H]neurotensin, that a majority of these are situated in the entorhinal area and that despite some differences in the regional distribution of these binding sites within the hippocampal region, some principal similarities may exist between these species.

Animals↗
PubMed1985

Potential neuroleptic agents. 3. Chemistry and antidopaminergic properties of substituted 6-methoxysalicylamides.

A series of substituted 6-methoxysalicylamides were synthesized from their corresponding 2,6-dimethoxybenzamides by demethylation of one methoxy group with boron tribromide. Substituted 6-methoxysalicylamides having a lipophilic aromatic substituent in the 3-position para with respect to the methoxy group, e.g. a bromo or an iodo atom or an ethyl or a propyl group, and having an (S)-N-(1-alkyl-2-pyrrolidinyl)methyl moiety as the side chain were found to be potent blockers of [3H]spiperone binding in vitro and potent inhibitors of the apomorphine syndrome in the rat. Similar to remoxipride but in contrast to haloperidol, some of the substituted salicylamides show a 10-20-fold separation between the dose that inhibits hyperactivity and that which inhibits stereotypy. It was concluded that, besides the requirement of a lipophilic substituent in the position para to the methoxy group for antidopamine activity in vivo, the formation of a coplanar six-membered pseudoring involving the amide moiety and the methoxy group is a structural requirement for activity in vitro.

Animals↗
PubMed1985

Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography.

Two substituted benzamides, FLB 524 and raclopride, were labeled with 11C and examined for their possible use as ligands for positron emission tomography (PET)-scan studies on dopamine-2 (D-2) receptors in the brains of monkeys and healthy human subjects. Both ligands allowed the in vivo visualization of D-2 receptor binding in the corpus striatum caudate nucleus/putamen complex in PET-scan images. [11C]Raclopride showed a high ratio of specific striatal to nonspecific cerebellar binding, and the kinetics of binding of this ligand made it optimal for PET studies. The in vivo binding of [11C]raclopride in the striatum of cynomolgus monkeys was markedly reduced by displacement with haloperidol. This and previous in vitro data indicate that [11C]raclopride binds selectively to striatal D-2 dopamine receptors. In healthy human subjects, [11C]raclopride binding in the caudate nucleus/putamen was 4- to 5-fold greater than nonspecific binding in the cerebellum. In comparison with previously available ligands for PET-scan studies on central dopamine receptors in man, [11C]raclopride appears to be advantageous with regard to (i) specificity of binding to D-2 receptors, (ii) the high ratio between binding in dopamine-rich (caudate, putamen) and dopamine-poor (cerebellum) human brain regions, and (iii) rapid association and reversibility of specific binding. [11C]Raclopride should be a valuable tool for characterizing D-2 receptors in the brains of patients with neuropsychiatric disorders.

Animals↗
PubMed1985

"Specific" binding of [3H]imipramine to protease-sensitive and protease-resistant sites.

A number of 5-hydroxytryptamine (5-HT) uptake inhibitors have been shown to displace the binding of [3H]imipramine to rat cortical membranes in a complex manner with Hill slopes less than unity. Norzimeldine displaced the binding of [3H]imipramine in a biphasic manner with IC50 values for the two components of about 30 nM and 30 microM. This latter site alone was found in tissues that had been treated with a protease. Binding to both of these sites was displaced by 10 microM desipramine. The protease-sensitive [3H]imipramine binding sites were found to be saturable, high-affinity binding sites with a KD of 8 nM. The number of these sites varied between brain regions and was positively correlated with the regional distribution of [14C]5-HT but not [3H]noradrenaline uptake. This was not the case however for the protease-resistant but desipramine-displaceable binding sites. Since most previous [3H]imipramine binding studies have been performed with high concentrations of desipramine (10 microM) to define "specific binding," these data would suggest that either protease-sensitivity or displacability by 1 microM norzimeldine would give more reliable estimates of the specific binding.

Animals↗
PubMed1985

[Selective antidopaminergic properties of remoxiprid, a new potential antipsychotic agent].

The pharmacology of S-(-)-3-bromo-2, 6-dimethoxy-N-(1-ethyl-2-pyrrolidinylone-ethyl)-benzamide (remoxipride), a new neuroleptic compound belonging to the benzamide group, has been thoroughly investigated using a number of different techniques. The compound blocks apomorphine-induced stereotypies and hyperactivity, indicating potent antidopaminergic activity. However, in contrast to many other antidopaminergic compounds, remoxipride induces only weak and atypical catalepsy, which indicates that remoxipride might exert less antidopaminergic side effects than other neuroleptic drugs. In vivo receptor binding studies using 3H-spiperone show that remoxipride preferentially blocks dopamine receptors only are blocked to 60% even at very high doses. In vitro receptor binding studies show that remoxipride is devoid of affinity for receptors other than the dopamine D2 receptors except at higher concentrations. These results indicate that remoxipride should be a clinically effective neuroleptic compound exerting less extrapyramidal side effects than the neuroleptics currently used.

Animals↗
PubMed1984

Remoxipride, a new potential antipsychotic compound with selective antidopaminergic actions in the rat brain.

The novel substituted benzamide, remoxipride, preferentially blocked apomorphine-induced hyperactivity with weak effects on stereotypies. The potency of remoxipride was about 50 times higher than that of sulpiride. Remoxipride caused a weak, atypical form of catalepsy and showed a high separation between the ED50 for blockade of apomorphine-induced hyperactivity and the ED50 for induction of catalepsy (ratio 24). Remoxipride was shown to be a selective dopamine D2 receptor antagonist since it displaced [3H]spiperone (IC50 = 1570 nM) but not [3H]flupentixol (IC50 greater than 100 000 nM) in rat striatum, and did not inhibit striatal DA-sensitive adenylate cyclase in vitro (IC50 greater than 100 000 nM). Remoxipride is a potent antagonist of D2 receptors showing a dose-dependent blockade of [3H]spiperone and [3H]n-propylnorapomorphine in vivo binding with a potency equal to that of chlorpromazine. In contrast to haloperidol, remoxipride caused a preferential blockade of in vivo [3H]spierone binding in the mesolimbic DA rich areas and the substantia nigra with much less effect in the striatum. In addition, remoxipride produced a preferential increase of DA utilization following synthesis inhibition in the olfactory tubercle. Only minor changes in NA and 5-HT metabolism were observed while HVA and DOPAC levels were markedly elevated. Taken together, these results indicate that remoxipride is a potent, selective D2 receptor blocking agent with a preferential action in mesolimbic and extrastriatal dopamine-containing neurons.

Adenylyl Cyclases↗
PubMed1984

Effects of antidepressant drugs on histamine-H1 receptors in the brain.

The histamine-H1 receptor blocking properties of a number of structurally different antidepressant drugs have been evaluated using a 3H-mepyramine binding assay and a guinea-pig ileum preparation. The tricyclic antidepressants all inhibited the histamine-H1 receptor. Some newer antidepressant drugs, such as zimelidine and nomifensine were devoid of activity while others, such as iprindole and mianserin were very potent. It is concluded that antagonistic effects on the histamine-H1 receptor is not associated with the therapeutic efficacy in depression, but may contribute to the sedative effects of the antidepressant drugs.

Animals↗
PubMed1984

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants on beta-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex.

The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of beta-adrenoceptors and 5-HT2 binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in beta-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the beta-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the beta-adrenoceptor produced by these compounds. Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT2 binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT2 binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were unaffected by pretreatment with DSP4.

Alanine↗
PubMed1984

Alaproclate, a new selective 5-HT uptake inhibitor with therapeutic potential in depression and senile dementia.

Alaproclate, a new specific 5-HT uptake inhibitor, was examined for its action on several receptors in the brain, for its action on the NA, DA and 5-HT uptake mechanisms in vivo and for its action on brain biogenic amine content. Alaproclate was practically devoid of action on a number of receptors as examined in binding studies in vitro: 5-HT, histamine-H1, alpha 1, -alpha 2-adrenergic and dopamine D2 receptors. Alaproclate had also a weak affinity for 3H-norzimeldine binding sites in contrast to imipramine. Unlike the tricyclic antidepressants alaproclate had a negligible action on muscarinic receptors and failed to block muscarinic induced stimulation in vivo. Contrary to clomipramine alaproclate failed to block NA uptake in vivo. Alaproclate was found to display a regional selectivity in blocking 5-HT uptake in vivo (measured with the H 75/12-method). The compound was most potent in the hippocampus and hypothalamus followed by striatum and cerebral cortex with a low potency in the spinal cord. The results are discussed in relation to a previously presented carrier site model for serotonin reuptake.

Alanine↗
PubMed1984

Platelet and fibroblast monoamine oxidase in alcoholism.

Monoamine oxidase (MAO) activity has been reported to be low in platelets (MAO B) and brain (MAO A and B) of some patients with alcoholism compared to control subjects. Whether the decreased platelet MAO activity found in alcoholism is secondary to the effect of alcohol or exists before alcohol abuse is not clear. The hypothesis that altered MAO A activity is determined by an abnormality in the genetic regulation of the enzyme can be tested by measuring MAO A activity in human fibroblasts cultured under controlled conditions. We first studied the kinetic parameters of platelet MAO B activity in patients hospitalized for treatment of alcoholism. Vmax was 38% lower in the patients (n = 14) than in normal controls (n = 22), but the enzyme affinity (Km) for the substrate tyramine was unchanged. Patients with the five lowest levels of platelet MAO activity had MAO activity measured from fibroblasts cultured from skin punch biopsies. Their fibroblast MAO activity was within the normal range, showing a dissociation between platelet MAO B and fibroblast MAO A activities and suggesting that MAO A activity is not low for genetic reasons in alcoholic subjects who do have low platelet MAO B activity.

Alcoholism↗