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Biomedical subjects

G Giannaccini

Publications and source records attributed to G Giannaccini.

At least 55 records · Page 3Linked to original sources
PubMed1997

HPLC resolution of C5 chiral 4,5-dihydro-1,4-benzodiazepines: stereochemical characterization and enantioselective GABAA receptor binding.

HPLC resolution on chiral stationary phases has been successfully employed to obtain single enantiomers of C5 chiral 4,5-dihydro-1,4-benzodiazepines and to determine the enantiomeric composition of the collected stereoisomeric fractions. The absolute configuration of the prevailing enantiomer has been assigned on the basis of the circular dichroism spectra, as compared with that of the structural analogue (5R)- and (5S)-dihydrodiazepam. The single enantiomers, assayed for their binding to the central nervous system receptor, showed relatively low affinity but significant differences in displacing radioactively labelled flunitrazepam from specific benzodiazepine site. GABA shift experiments allowed the classification of these benzodiazepines as partial agonist or antagonist.

Benzodiazepines↗
PubMed1997

[3H]ketanserin binding in human brain postmortem.

This study aimed at comparing the binding characteristics of [3H]ketanserin, a high-affinity serotonin 2A (5-HT2A) receptor antagonist, in the prefrontal cortex, hippocampus and striatum of human brain post-mortem. The results indicated the presence of a single population of binding sites in all the regions investigated, with no statistical difference in maximum binding capacity (B(max)) or dissociation constant (K(d)) values. The pharmacological profile of [3H]ketanserin binding was consistent with the labeling of the 5-HT2A receptor, since it revealed a competing drug potency ranking of ketanserin = spiperone > clozapine = haloperidol > methysergide > mesulergine > 5-HT. In conclusion, the 5-HT2A receptor, as labeled by [3H]ketanserin, would seem to consist of a homogenous population of binding sites and to be equally distributed in human prefronto-cortical, limbic and extrapyramidal structures.

Autopsy↗
PubMed1996

Synthesis, structure-activity relationships, and molecular modeling studies of N-(indol-3-ylglyoxylyl)benzylamine derivatives acting at the benzodiazepine receptor.

A number of N-(indol-3-ylglyoxylyl)benzylamine derivatives were synthesized and tested for [3H]flunitrazepam displacing activity in bovine brain membranes. Some of these derivatives (9, 12, 14, 15, 17, 27, 34, 35, 38, 41, and 45) exhibited high affinity for the benzodiazepine receptor (BzR) with Ki values ranging from 67 to 11 nM. The GABA ratio and [35S]-tert-butylbicyclophosphorothionate binding data, determined for the most active compounds, showed that they elicit an efficacy profile at the BzR which depends on the kind of substituent present on the phenyl ring of the benzylamine moiety. Moreover, lengthening (propylamine derivatives 1-3) and shortening (aniline derivatives 46-54) of the distance between the phenyl ring and the amide group of the side chain gave compounds with a drastically lower binding potency. The biological results are discussed in the light of a recently proposed pharmacophore model and compared, by molecular modeling studies, with those obtained from effective BzR ligands.

Animals↗
PubMed1996

Binding of beta 1-adrenoceptor antagonist [3H]CGP 26505 in rat cerebral cortex and sinus atrial node.

Specific beta 1-adrenoceptors antagonist [3H]CGP 26505 binding was characterized in rat cerebral cortex and heart sinus atrial node. In both tissues [3H]CGP 26505 binding was maximal at 25 degrees C, it was specific, saturable and protein concentration dependent. Scatchard analysis of saturation isotherms of specific [3H]CGP 26505 binding in cerebral cortex showed that [3H]CGP 26505 binds a single class of high affinity sites with a dissociation constant (KD) of 1 +/- 0.3 nM and a maximal number of binding sites (Bmax) of 40 +/- 2 fmol/mg of protein. In sinus atrial node, [3H]-CGP 26505 binds a single class of high affinity sites (KD = 1.9 +/- 0.4 nM, Bmax = 28 +/- 2 fmol/mg of protein).

Adrenergic beta-Antagonists↗
PubMed1996

The serotonin transporter from human brain: purification and partial characterization.

The serotonin (5-HT) transporter from human striatum was solubilized by digitonin and purified by affinity chromatography. The native protein-detergent complex had a molecular mass of 205 kDa, as estimated by gel-exclusion chromatography of the eluates obtained from affinity chromatography. The purified 5-HT transporter migrated as a single band of 67 kDa in SDS-PAGE. To clarify the spatial relationships between the binding sites of the tricyclic antidepressants, as [3H]-imipramine, and of the selective serotonin reuptake inhibitors, as [3H]-paroxetine, on the 5'HT transporter, both radioligands were used to label it in the purification steps. [3H]-paroxetine bound with the same affinity to a single high-affinity site on both membrane and purified preparations. [3H]-imipramine labeled a high- and a low-affinity site on parent membranes, whereas it bound to a single high-affinity site on the purified extract. Tricyclic antidepressants, selective serotonin reuptake inhibitors and 5-HT itself displaced [3H]-paroxetine and [3H-]imipramine from their high-affinity binding sites on both the membrane-bound and the purified 5-HT transporter in a monophasic fashion with Hill coefficients close to unity. Furthermore, both [3H]-paroxetine and [3H]-imipramine displayed a similar maximum binding capacity on an identical protein of 205 kDa. Our results suggest overlapping binding sites for tricyclic antidepressants, selective serotonin reuptake inhibitors and 5-HT on the 5-HT transporter.

Antidepressive Agents, Tricyclic↗
PubMed1996

Benzodiazepine binding inhibitory activity: new supportive findings on its presence in psychiatric patients and further biochemical analyses.

The authors investigated the presence of a serum activity inhibiting the specific binding of 3H-flunitrazepam (which labels the central benzodiazepine receptors) (BBIA) in patients with different psychiatric disorders and analyzed it by means of high performance liquid chromatography (HPLC) analysis. The results showed that the lowest activity was present in healthy controls who were not different from patients with schizophrenia and obsessive-compulsive disorder. On the contrary, the BBIA values of these 3 groups of patients were significantly lower than those found in patients with bipolar disorder in various phases (depressive, mixed or manic), in unipolar depressives and in patients with panic and delusional disorders. The HPLC analysis of the serum extracts revealed the presence of 3 peaks of activity which were differently distributed in the patients and in the healthy controls, peak 3 being totally absent in the last group and mainly represented in bipolar depressives. The GABA ratio values showed that peaks 1 and 2 behave as agonists while peak 3 behaves as an inverse agonist. The mass fragmentography of the different peaks is in progress.

Adult↗
PubMed1996

Decreased platelet 3H-paroxetine binding in obsessive-compulsive patients.

The similarities between the serotonin (5-HT) transporter in both human platelets and human brain permit us to investigate this structure in patients with different psychiatric disorders. Several reports have shown abnormalities of the 5-HT transporter, by means of the measurement of the 5-HT uptake or of the 3H-imipramine binding, in platelets of patients with obsessive-compulsive disorder (OCD). The availability of the ligand 3H-paroxetine, a selective 5-HT reuptake inhibitor, to label the 5-HT transporter, promoted us to evaluate the binding of 3H-paroxetine in platelets of 18 drug-free patients with OCD. The results, showing that the patients had a lower number of 3H-paroxetine sites, which is inversely correlated with the Yale Brown Obsessive-Compulsive Scale total score, than a similar group of controls, add supporting evidence to the involvement of 5-HT in OCD. In addition, the decreased functionality of the 5-HT transporter seems to be linked to the severity of OC symptoms.

Adolescent↗
PubMed1996

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. X--Synthesis and inhibition of benzodiazepine receptor binding of new 1,4-thiazine and 1,5-thiazepine polycondensed heterocycles with steroidal structure.

Some naphtho[1,2,-b]-s-triazolo[4,3-d]-1,4-thiazine and 1,5-thiazepine and s-triazolo[4', 3'-4,5]-1,4-thiazino[3,2-c]quinoline derivatives have been synthesized and tested for their ability to displace [3H]RO 15-1788 binding from bovine brain membranes. Several compounds showed moderate binding affinity for the benzodiazepine receptor.

Animals↗
PubMed1995

Benzodiazepine agonists reverse the effects of noise exposure on central benzodiazepine receptors and cardiac responsiveness.

Rats were submitted to 110 dB white noise exposure for 1, and 6 hours and brain alpha 1, beta 1 and benzodiazepine receptor binding was evaluated with selective ligands. An increase in cerebral benzodiazepine receptor (CBR) concentration, without any significant change in affinity constant, occurred after the 6 h treatment; no change was observed in adrenergic receptor binding at any period of exposure. Both diazepam and clonazepam pre-treatment reversed the effects of noise on CBR binding, confirming a role of these receptors in the response to noise stress. Furthermore, these benzodiazepine agonists influenced the response of cardiac and aortic tissues, which are known to be changed by stress exposure. Diazepam and clonazepam pre-treatment protected cardiac tissue from the effects of 6h noise stress, and a potentiation of aortic responses was detected, although at different times of exposure. The differences between the responses of these peripheral tissues to benzodiazepine treatment suggest that the expression depends on the tissue examined and the period of exposure.

Animals↗
PubMed1994

Solubilization and characterization of [3H]imipramine and [3H]paroxetine binding sites from calf striatum.

The serotonin (5-HT) transporter from calf striatum cerebral membranes was solubilized with digitonin and characterized by gel exclusion chromatography. [3H]Imipramine and [3H]paroxetine were utilized as markers for labeling it. 3H-imipramine labels a high- and a low-affinity site on striatum membranes, whereas it binds to a single high-affinity site on the solubilized fraction. [3H]Paroxetine binds with the same affinity to a single site on both membranes and solubilized preparations. After gel exclusion chromatography of the solubilizate both [3H]imipramine and [3H]paroxetine bind on an identical fraction of 205 kDa molecular weight, with a similar maximum number of binding sites (Bmax). Our results suggest that both 3H-imipramine and [3H]paroxetine bind to a common site on the 5-HT transporter.

Animals↗
PubMed1994

Changes in peripheral benzodiazepine receptors in patients with panic disorder and obsessive-compulsive disorder.

Peripheral benzodiazepine (BDZ) receptors were investigated through the binding of the specific ligand 3H-PK-11195 to platelet membranes, in 17 patients suffering from panic disorder (PD) and in 16 patients affected by obsessive-compulsive disorder (OCD). The results, showing that the density (Bmax) of peripheral BDZ receptors was significantly lower in patients with PD than in controls or OC patients, suggest that the number of platelet BDZ receptors varies with different anxiety disorders and that perhaps this marker may be beneficial in differentiating some subtypes of these disorders.

Adolescent↗
PubMed1994

Age-related changes in peripheral benzodiazepine receptors of human platelets.

Using 3H-PK 11195 as radioligand, the number and affinity of peripheral benzodiazepine receptors in platelets of 15 elderly healthy subjects were compared to those of 15 young subjects. The results showed that the dissociation constant (Kd) was significantly higher in the elderly than in the young subjects, while the density of binding sites did not differ. These findings suggest that the age-related changes in peripheral benzodiazepine receptors may be coupled with secondary changes in their hypothesized functions.

Adult↗
PubMed1993

The peripheral-type benzodiazepine receptor ligands [3H]Ro 5-4864 and [3H]PK 11195 bind to the retina of rabbit, but not of turtle.

The binding of [3H]flunitrazepam, [3H]Ro 5-4864, and [3H]PK 11195 to membrane preparations of the retina was studied in the turtle and rabbit. Only a single population of [3H]flunitrazepam binding sites was detected in the turtle, whereas two populations appeared to be present in the rabbit. No specific binding for [3H]Ro 5-4864 and [3H]PK 11195 could be detected in the turtle. In rabbit, both ligands bound with high affinity, revealing a significant population of binding sites (KD values of 24 +/- 2.3 and 2.2 +/- 0.8 nM, and Bmax values of 440 +/- 35 and 1,482 +/- 110 fmol/mg of protein, respectively). The binding was temperature- and protein-dependent. Displacement studies showed a similar rank order of potency of various unlabeled ligands against both [3H]Ro 5-4864 and [3H]PK 11195 (PK 11195 > Ro 5-4864 > flunitrazepam > flumazenil). These results suggest that peripheral-type benzodiazepine receptors are present in the retina of the rabbit, but not of the turtle.

Animals↗
PubMed1992

Benzodiazepine receptor affinity and interaction of some N-(indol-3-ylglyoxylyl)amine derivatives.

Several derivatives, in which tryptamine, tyramine, and dopamine moieties are linked to the indole nucleus by an oxalyl bridge, were tested for their ability to displace the specific binding of [3H]flunitrazepam from bovine brain membranes. GABA ratio and in vivo tests for the most potent compounds showed they behave as inverse agonists at the benzodiazepine receptor (BzR). To better define the structure-activity relationship (SAR) of this kind of ligand, several phenylethylamine derivatives were synthesized to evaluate their affinity to BzR. Some of these derivatives (17, 21, 24, 26, and 30) were found to exhibit high affinity (Ki = 0.51-0.085 microM) for BzR and possessed a partial agonist activity, although their chemical structure is closely related to tryptamine 2-6, tyramine 7-11, and dopamine 12-16 derivatives. A different interaction of these ligands to the receptor site is hypothesized. Moreover, all the prepared 1-methyl derivatives exhibited very low binding affinity to BzR.

Animals↗
PubMed1992

Binding of the benzodiazepine ligand [3H]-RO 15-1788 to membrane preparations of the rabbit and turtle retina.

1. We have studied the binding of [3H]-RO 15-1788 to membrane preparations of the retina of rabbit (Lepus cunicula) and turtle (Pseudemys scripta elegans). 2. In both species, [3H]-RO 15-1788 binding was maximal at 0 degrees C and decreased with increasing temperature. It was saturable, protein concentration-dependent and specific. Flunitrazepam, unlabelled RO 15-1788 and ethyl-beta-carboline were the most effective displacers, whereas RO 5,4864 was ineffective. 3. In both turtle and rabbit retina, Scatchard analysis indicated the presence of a single binding site for [3H]-RO 15-1788. The KD was 0.75 nM in both turtle and rabbit, while the Bmax were 520 and 250 fmol/mg protein in turtle and rabbit respectively. A study of the association rate of [3H]-RO 15-1788 binding revealed faster kinetics in turtle, as compared to rabbit.

Animals↗
PubMed1992

Tricyclic heteroaromatic systems. Synthesis and benzodiazepine binding activity of 1-substituted-3-methyl- and 3-phenylpyrazolo[4,5-c]quinolin-4-ones.

The synthesis and the benzodiazepine binding activity of some 3-methyl- and 3-phenylpyrazolo[4,5-c]quinolin-4-ones bearing a heterocyclic or a substituent which is different from an aryl moiety at position-1 are reported. Molecular modelling is used to correlate the binding affinity to the chemical features and to justify the reduced receptor affinities of the reported compounds with respect to that of CGS 8216 which is taken as the lead compound.

Animals↗
PubMed1991

Platelet peripheral benzodiazepine receptors are decreased in Parkinson's disease.

Peripheral benzodiazepine (BDZ) receptors are located in a variety of tissues, including platelets, in the nuclear and/or mitochondrial membranes. We studied the density of peripheral BDZ receptors in platelets of 10 de novo Parkinson's disease (PD) patients, 18 PD patients treated with a levodopa/carbidopa combination, and in 15 healthy subjects matched for sex and age. The binding assay was conducted using [3H]PK 11195, a specific ligand for peripheral BDZ receptors. A significant decrease in the density of [3H]PK 11195 binding sites has been observed in PD patients with respect to controls (p less than 0.01), but not between de novo and treated PD patients. No correlation has been found between the decrease in density of [3H]PK 11195 binding sites in platelets and either the duration or severity of PD. Peripheral BDZ receptors are implicated in the regulation of mitochondrial respiratory function. Thus, their decrease in PD might parallel the abnormalities in mitochondrial function recently found in this neurologic disease.

Aged↗