Effects of haloperidol and clozapine on synapse-related gene expression in specific brain regions of male rats

We investigated the effects of clozapine and haloperidol, drugs that are widely used in the treatment of schizophrenia, on gene expression in six cortical and subcortical brain regions of adult rats. Drug treatments started at postnatal day 85 and continued over a 12-week period. Ten animals received haloperidol (1 mg/kg bodyweight) and ten received clozapine (20 mg/kg bodyweight) orally each day. Ten control rats received no drugs. The ten genes selected for this study did not belong to the dopaminergic or serotoninergic systems, which are typically targeted by the two substances, but coded for proteins of the cytoskeleton and proteins belonging to the synaptic transmitter release machinery. Quantitative real-time PCR was performed in the prelimbic cortex, cingulate gyrus (CG1) and caudate putamen and in the hippocampal cornu ammonis 1 (CA1), cornu ammonis 3 (CA3) and dentate gyrus. Results show distinct patterns of gene expression under the influence of the two drugs, but also distinct gene regulations dependent on the brain regions. Haloperidol-medicated animals showed statistically significant downregulation of SNAP-25 in CA3 (p = 0.0134) and upregulation of STX1A in CA1 (p = 0.0133) compared to controls. Clozapine-treated animals showed significant downregulation of SNAP-25 in CG1 (p = 0.0013). Our results clearly reveal that the drugs' effects are different between brain regions. These effects are possibly indirectly mediated through feedback mechanisms by proteins targeted by the drugs, but direct effects of haloperidol or clozapine on mechanisms of gene expression cannot be excluded

Sterically Crowded Tin Acenaphthenes

The synthesis of crowded peri-5-bromo-6-(organostannyl)acenaphthenes is described. Reaction of 5,6-dibromoacenaphthene with 1 equiv of n-BuLi at -40 degrees C in diethyl ether followed by addition of the appropriate organotin reagent at 0 degrees C gave 5-bromo-6-(triphenylstannyl)acenaphthene (1), S-bromo-6-(chlorodiphenylstannyl)acenaphthene (2), bis(6-bromoacenaphthen-5-yl)diphenylstannane (3), bis(6-bromoacenaphthen-5-yl)dibenzylstannane (4), bis(6-bromoacenaphthen-5-yl)dibutylstannane (6), and bis(6-bromoacenaphthen-5-yl)dichlorostannane (7) in low to medium yields (10-56%). 4 was converted into 5-iodo-6-bromoacenaphthene (5) by stirring overnight in the presence of a large excess of iodine. The new compounds were fully characterized spectroscopically. Sn-119 NMR spectra suggest and interaction between the tin atoms and the neighboring pen halogen atoms. Single-crystal X-ray studies on 1-4 and 6-8 revealed Sn center dot center dot center dot X distances which are significantly less than the sum of the van der Waals radii, while DFT calculations indicate Wiberg bond indices of up to 0.11. Furthermore, there is evidence of the onset of 3c-4e bonding, though according to natural population analysis, the charge on tin is close to +2 in all compounds studied. Electrostatic interactions may thus be another important driving force for the close Br center dot center dot center dot Sn interactions, along with the small covalent (donor-acceptor) contributions

Synthetic, Structural, and Spectroscopic Studies of Sterically Crowded Tin–Chalcogen Acenaphthenes

A series of sterically encumbered <i>peri</i>-substituted acenaphthenes have been prepared containing chalcogen and tin moieties at the close 5,6-positions (Acenap­[SnPh₃]­[ER], Acenap = acenaphthene-5,6-diyl, ER = SPh (<b>1</b>), SePh (<b>2</b>), TePh (<b>3</b>), SEt (<b>4</b>); Acenap­[SnPh₂Cl]­[EPh], E = S (<b>5</b>), Se (<b>6</b>); Acenap­[SnBu₂Cl]­[ER], ER = SPh­(<b>7</b>), SePh (<b>8</b>), SEt (<b>9</b>)). Two geminally bis­(<i>peri</i>-substituted) derivatives ({Acenap­[SPh₂]}₂SnX₂, X = Cl (<b>10</b>), Ph (<b>11</b>)) have also been prepared, along with the bromo–sulfur derivative Acenap­(Br)­(SEt) (<b>15</b>). All 11 chalcogen–tin compounds align a Sn–C_Ph/Sn–Cl bond along the mean acenaphthene plane and position a chalcogen lone pair in close proximity to the electropositive tin center, promoting the formation of a weakly attractive intramolecular donor–acceptor E···Sn–C_Ph/E···Sn–Cl 3c-4e type interaction. The extent of E→Sn bonding was investigated by X-ray crystallography and solution-state NMR and was found to be more prevalent in triorganotin chlorides <b>5</b>–<b>9</b> in comparison with triphenyltin derivatives <b>1</b>–<b>4</b>. The increased Lewis acidity of the tin center resulting from coordination of a highly electronegative chlorine atom was found to greatly enhance the lp­(E)−σ*­(Sn–Y) donor–acceptor 3c-4e type interaction, with substantially shorter E–Sn <i>peri</i> distances observed in the solid state for triorganotin chlorides <b>5</b>–<b>9</b> (∼75% ∑<i>r</i>_vdW) and significant ¹<i>J</i>(¹¹⁹Sn,⁷⁷Se) spin–spin coupling constants (SSCCs) observed for <b>6</b> (163 Hz) and <b>8</b> (143 Hz) in comparison to that for the triphenyltin derivative <b>2</b> (68 Hz). Similar observations were observed for geminally bis­(<i>peri</i>-substituted) derivatives <b>10</b> and <b>11</b>

Sterically Crowded Tin Acenaphthenes

The synthesis of crowded <i>peri</i>-5-bromo-6-(organostannyl)­acenaphthenes is described. Reaction of 5,6-dibromoacenaphthene with 1 equiv of <i>n</i>-BuLi at −40 °C in diethyl ether followed by addition of the appropriate organotin reagent at 0 °C gave 5-bromo-6-(triphenylstannyl)­acenaphthene (<b>1</b>), 5-bromo-6-(chlorodiphenylstannyl)­acenaphthene (<b>2</b>), bis­(6-bromoacenaphthen-5-yl)­diphenylstannane (<b>3</b>), bis­(6-bromoacenaphthen-5-yl)­dibenzylstannane (<b>4</b>), bis­(6-bromoacenaphthen-5-yl)­dibutylstannane (<b>6</b>), and bis­(6-bromoacenaphthen-5-yl)­dichlorostannane (<b>7</b>) in low to medium yields (10–56%). <b>4</b> was converted into 5-iodo-6-bromoacenaphthene (<b>5</b>) by stirring overnight in the presence of a large excess of iodine. The new compounds were fully characterized spectroscopically. ¹¹⁹Sn NMR spectra suggest and interaction between the tin atoms and the neighboring peri halogen atoms. Single-crystal X-ray studies on <b>1</b>–<b>4</b> and <b>6</b>–<b>8</b> revealed Sn···X distances which are significantly less than the sum of the van der Waals radii, while DFT calculations indicate Wiberg bond indices of up to 0.11. Furthermore, there is evidence of the onset of 3c–4e bonding, though according to natural population analysis, the charge on tin is close to +2 in all compounds studied. Electrostatic interactions may thus be another important driving force for the close Br···Sn interactions, along with the small covalent (donor–acceptor) contributions

Sterically Crowded Tin Acenaphthenes

The synthesis of crowded <i>peri</i>-5-bromo-6-(organostannyl)­acenaphthenes is described. Reaction of 5,6-dibromoacenaphthene with 1 equiv of <i>n</i>-BuLi at −40 °C in diethyl ether followed by addition of the appropriate organotin reagent at 0 °C gave 5-bromo-6-(triphenylstannyl)­acenaphthene (<b>1</b>), 5-bromo-6-(chlorodiphenylstannyl)­acenaphthene (<b>2</b>), bis­(6-bromoacenaphthen-5-yl)­diphenylstannane (<b>3</b>), bis­(6-bromoacenaphthen-5-yl)­dibenzylstannane (<b>4</b>), bis­(6-bromoacenaphthen-5-yl)­dibutylstannane (<b>6</b>), and bis­(6-bromoacenaphthen-5-yl)­dichlorostannane (<b>7</b>) in low to medium yields (10–56%). <b>4</b> was converted into 5-iodo-6-bromoacenaphthene (<b>5</b>) by stirring overnight in the presence of a large excess of iodine. The new compounds were fully characterized spectroscopically. ¹¹⁹Sn NMR spectra suggest and interaction between the tin atoms and the neighboring peri halogen atoms. Single-crystal X-ray studies on <b>1</b>–<b>4</b> and <b>6</b>–<b>8</b> revealed Sn···X distances which are significantly less than the sum of the van der Waals radii, while DFT calculations indicate Wiberg bond indices of up to 0.11. Furthermore, there is evidence of the onset of 3c–4e bonding, though according to natural population analysis, the charge on tin is close to +2 in all compounds studied. Electrostatic interactions may thus be another important driving force for the close Br···Sn interactions, along with the small covalent (donor–acceptor) contributions

Synthetic, structural, and spectroscopic studies of sterically crowded tin-chalcogen acenaphthenes

The work in this project was supported by the Engineering and Physical Sciences Research Council (EPSRC) and EaStCHEM.A series of sterically encumbered peri-substituted acenaphthenes have been prepared containing chalcogen and tin moieties at the close 5,6-positions (Acenap[SnPh3][ER], Acenap = acenaphthene-5,6-diyl, ER = SPh (1), SePh (2), TePh (3), SEt (4); Acenap[SnPh2Cl][EPh], E = S (5), Se (6); Acenap[SnBu2Cl][ER], ER = SPh(7), SePh (8), SEt (9)). Two geminally bis(peri-substituted) derivatives ({Acenap[SPh2]}2SnX2, X = Cl (10), Ph (11)) have also been prepared, along with the bromo–sulfur derivative Acenap(Br)(SEt) (15). All 11 chalcogen–tin compounds align a Sn–CPh/Sn–Cl bond along the mean acenaphthene plane and position a chalcogen lone pair in close proximity to the electropositive tin center, promoting the formation of a weakly attractive intramolecular donor–acceptor E···Sn–CPh/E···Sn–Cl 3c-4e type interaction. The extent of E→Sn bonding was investigated by X-ray crystallography and solution-state NMR and was found to be more prevalent in triorganotin chlorides 5–9 in comparison with triphenyltin derivatives 1–4. The increased Lewis acidity of the tin center resulting from coordination of a highly electronegative chlorine atom was found to greatly enhance the lp(E)−σ*(Sn–Y) donor–acceptor 3c-4e type interaction, with substantially shorter E–Sn peri distances observed in the solid state for triorganotin chlorides 5–9 (∼75% ∑rvdW) and significant 1J(119Sn,77Se) spin–spin coupling constants (SSCCs) observed for 6 (163 Hz) and 8 (143 Hz) in comparison to that for the triphenyltin derivative 2 (68 Hz). Similar observations were observed for geminally bis(peri-substituted) derivatives 10 and 11.PostprintPeer reviewe