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Biarylboronic esters are generally prepared by directed ortho-metalation or by Miyaura borylation and hence rely on the presence of a directing group or pre-functionalization. In this paper, the preparation of biarylboronic esters by direct C-H borylation of biaryl substrates is reported. Sterically governed regioselectivities were observed in the borylation of appropriately substituted biaryls by using [Ir(OMe)(COD)]2 precatalyst and di-tert-butylbipyridyl ligand. The resulting biarylboronic esters were isolated in 38-98% yields. The synthesized biarylboronic esters were further successfully employed in C-O, C-Br, and C-C coupling reactions. [ABSTRACT FROM AUTHOR]

Iridium-catalyzed aromatic borylation provides quick onestep access to 2,6-bis(trifluoromethyl)pyridine-4-boronic acid pinacol ester. Suzuki couplings of this highly electron-deficient pyridine-4-boronic ester with various (hetero)aryl bromides was successfully carried out and the coupled products were obtained in 46–95% isolated yields. Double and triple Suzuki couplings, with dibromo- and tribromoarenes, respectively, were also achieved. Thus demonstrating that this pyridine- 4-boronic ester can be a useful source for the installation of one of the strongest electron-withdrawing aromatic group in organic compounds. [ABSTRACT FROM AUTHOR]

Pulp and oils (fruit extract) from Sea Buckthorn (Hippophae rhamnoides L. spp. Turkestanica) (HRL) seeds and berries have been traditionally used in the treatment of different clinical and psychotic disorders and have significant implication in contemporary medicinal therapy. Schizophrenia is a chronic severe mental illness that affects approximately 1% of the population. Although the first generation of antipsychotic drugs such as chlorpromazine and haloperidol are widely prescribed for the treatment of schizophrenia, their beneficial effects are accompanied by extrapyramidal side effects (EPS). The present study was designed to investigate the effects of oral supplementation of HRL fruit extract (HRL-FE) on behavioral deficits and changes in brain serotonin (5- hydroxytryptamine; 5-HT) metabolism in rats administered with haloperidol repeatedly (two times a day at 09:00-09:30 A.M. and 05:00-05:30 P.M. at dose of 3.0 mg/kg body weight for two weeks. Results revealed that after two weeks of oral administration of HRL-FE (4.0 mg/kg body weight), rats exhibited significant (p<0.01) increases in locomotor activity in home cages and exploratory activity in open field arena. Repeated haloperidol treatment significantly (p<0.01) decreased brain tryptophan (TRP) and 5-HT and these decreases were reversed by 4.0 mg/kg body weight HRL-FE. These data suggest that HRL-FE plays a modifying role against the haloperidol induced behavioral deficits and could further extend as a nutritive therapy to conventional antipsychotic treatment in schizophrenia. [ABSTRACT FROM AUTHOR]

The idea that serotonin (5-hydroxytryptamine; 5-HT) is contributed in schizophrenia has long been advocated and alterations in 5-HT neurotransmission has been hypothesized to modulate both the therapeutic and extrapyramidal symptoms (EPS) liability of conventional neuroleptics. The 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a preferential 5-HT1A ligand, has been reported to attenuate EPS functions of haloperidol in animals. In view of a possible role of 5-HT1A receptors in the management of EPS functions of a neuroleptic drug, the present study was designed to investigate behavioral responses of 8-OH-DPAT at a challenge dose of 0.5mg/kg in rats with subchronic haloperidol administration at a dose of 5mg/kg twice daily for 5 days. The intensity of 5-HT syndrome provoked by 8-OH-DPAT was taken as a measure of postsynaptic responses. In the present study administration of haloperidol at a dose of 5mg/kg twice daily for 5 days decreased locomotion significantly (p<0.01) in familiar (home cage) environment. Subchronic administration of haloperidol at the same dose elicited significant (p<0.01) cataleptic responses in rats when compared with saline treated rats. Results revealed that 8-OH-DPAT-induced hyperlocomotion (p<0.05) and forepaw treading (p<0.1) were significantly smaller in rats pre-treated with haloperidol for 5 days than repeatedly saline injected rats. Conversely, the other components of the syndrome i.e. flat body posture (p<0.001), hind limb abduction (p<0.001) and straub tail (p<0.01) were significantly greater in repeated haloperidol treated rats when compared with repeated saline injected rats. These findings help to demonstrate a causal link between the upregulation of DA-D2 receptors and the decrease in the effectiveness of presynaptic 5-HT1A receptors following subchronic haloperidol administration and this may further help to yield an antipsychotic agent with an improved profile of efficacy to EPS, thereby widening its therapeutic window. [ABSTRACT FROM AUTHOR]

The regioselectivities available through this convenient and efficient borylation reaction are complementary to those obtained by the electrophilic aromatic substitution reactions of fluoroalkoxyarenes. [ABSTRACT FROM AUTHOR]

Background: Long-term treatment of haloperidol, a neuroleptic, induces neurodegeneration specifically in the striatum (caudate and putamen), which plays an important role in the development of orofacial dyskinesia, a putative model of tardive dyskinesia (TD). This study investigated the protective effects of a concomitant treatment of aqueous fruit extract of Sea buckthorn (Hippophae rhamnoides L. spp. Turkestanica) (SBT-FE) (40 mg/kg, orally) plus haloperidol (3.0 mg/kg, ip) administration on an animal model of TD and on striatal neuronal alterations., Material/methods: Rats received daily haloperidol (3.0 mg/kg ip) and saline injections for 15 days. Seven-day posttreatment, aqueous SBT-FE (40 mg/kg) was administered daily via a feeding tube. Hypolocomotive effects (home cage activity, exploratory activity, catalepsy, and vacuous chewing movements) were monitored consecutively in each group. On the last day of the experiments, changes in extracellular levels of striatal dopamine (DA), dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) were determined by HPLC-EC., Results: Aqueous SBT-FE attenuated haloperidol-induced VCMs after second week of treatment and locomotor activity was greater in rats treated with SBT-FE compared with the controls. The results indicate that DA and HVA levels in the striatum were significantly (P <.01) altered in rats given SBT-FE before injections of haloperidol., Conclusions: Hippophae rhamnoides fruit extract has a protective role against haloperidol-induced orofacial dyskinesia. Consequently, use of Hippophae rhamnoides as a possible therapeutic agent for the treatment of tardive dyskinesia should be considered.

Objective: To investigate the effects of orally supplemented amino acids L-Tryptophan (Trp) and L-Valine (Val) in rats repeatedly injected with haloperidol following one week of drug withdrawal, with particular reference to extrapyramidal symptoms (EPS) and serotonin (5-hydroxytryptamine; 5-HT) metabolism in medial prefrontal cortex (mPFC)., Study Design: Experimental study., Place and Duration of Study: Department of Biochemistry, University of Karachi from December 2007 to February 2008., Methodology: The study was conducted on thirty six locally bred male Albino Wistar rats. Freshly prepared amino acids (Val and Trp) were added in the drinking water of rats on alternate days and haloperidol at doses of 5.0 mg/kg or saline were injected twice daily for three weeks following one week of withdrawal. Locomotor/ exploratory activities were scored in activity boxes and open field apparatuses. Catalepsy was monitored on an inclined surface. The animals tested for locomotor activity and catalepsy for two weeks follow-up post-injections plus one week of drug withdrawal were decapitated to collect mPFC regions of rat brain for neurochemical analysis by high performance liquid chromatography with electrochemical detection (HPLC-EC)., Results: There was significant increase (p<0.01) in locomotor activity in rats orally supplemented with Val and Trp following one week of drug withdrawal from repeated administration. Marked reduction in cataleptogenic effects of the drug was also observed. Significant (p<0.01) increases in the brain Trp and mPFC 5-HT metabolism in Val and Trp supplemented animals were also noticed., Conclusion: These findings help to demonstrate the effect of dietary amino acids, in particular, Trp to potentiate mPFC serotonergic modulation of neuroleptic activity.

The idea that serotonin (5-hydroxytryptamine; 5-HT) is contributed in schizophrenia has long been advocated and alterations in 5-HT neurotransmission has been hypothesized to modulate both the therapeutic and extrapyramidal symptoms (EPS) liability of conventional neuroleptics. The 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a preferential 5-HT(1A) ligand, has been reported to attenuate EPS functions of haloperidol in animals. In view of a possible role of 5-HT(1A) receptors in the management of EPS functions of a neuroleptic drug, the present study was designed to investigate behavioral responses of 8-OH-DPAT at a challenge dose of 0.5mg/Kg in rats with subchronic haloperidol administration at a dose of 5mg/Kg twice daily for 5 days. The intensity of 5-HT syndrome provoked by 8-OH-DPAT was taken as a measure of postsynaptic responses. In the present study administration of haloperidol at a dose of 5mg/Kg twice daily for 5 days decreased locomotion significantly (p<0.01) in familiar (home cage) environment. Subchronic administration of haloperidol at the same dose elicited significant (p<0.01) cataleptic responses in rats when compared with saline treated rats. Results revealed that 8-OH-DPAT-induced hyperlocomotion (p<0.05) and forepaw treading (p<0.1) were significantly smaller in rats pre-treated with haloperidol for 5 days than repeatedly saline injected rats. Conversely, the other components of the syndrome i.e. flat body posture (p<0.001), hind limb abduction (p<0.001) and straub tail (p<0.01) were significantly greater in repeated haloperidol treated rats when compared with repeated saline injected rats. These findings help to demonstrate a causal link between the upregulation of DA-D(2) receptors and the decrease in the effectiveness of presynaptic 5-HT(1A) receptors following subchronic haloperidol administration and this may further help to yield an antipsychotic agent with an improved profile of efficacy to EPS, thereby widening its therapeutic window.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-hydroxytryptamine 1A (serotonin; 5-HT1A) agonist was used to evaluate the role of somatodendritic and/or postsynaptic 5-HT1A receptors following exposure to restraint stress. Exposure to an episode of 2-h restraint stress decreased 24 h cumulative food intake. Intensity of 8-OH-DPAT-induced 5-HT syndrome monitored next day was smaller in restrained than unrestrained animals. Hyperphagic effects of 8-OH-DPAT were comparable in the two groups. Restrained animals injected with saline exhibited an increase in 5-HT levels in the hippocampus, hypothalamus and cortex but not in the midbrain and striatum. 5-Hydroxyindolacetic acid (5-HIAA) increased in the hippocampus, midbrain and cortex but not in the hypothalamus and striatum. 8-OH-DPAT injected at a dose of 0.25 mg/kg decreased 5-HT and 5-HIAA levels in different brain regions of unrestrained as well as restrained animals. The decreases were greater in restrained than unrestrained animals, suggesting a supersensitivity of somatodendritic 5-HT1A receptors. The results are discussed in the context of a role of 5-HT1A receptor in restraint-induced behavioral deficits.

Background: An important goal of current neuroleptic research is to develop antipsychotic compounds with a low incidence of extrapyramidal side effects (EPS). Clozapine, the first of the atypical antipsychotics to be proven effective in treatment-resistant schizophrenia, is reported to produce less EPS than typical neuroleptics, such as haloperidol., Material/methods: The present study compares the neurochemical profiles of clozapine and haloperidol in rats. Animals injected (i.p.) with haloperidol or clozapine were sacrificed 1h later to collect brain samples. Neurochemical estimations were carried out by HPLC-EC., Results: Administration of haloperidol at doses of 1.0, 2.5 and 5.0 mg/kg increased the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum and rest of the brain. Clozapine-injected rats (2.5, 5.0 and 10.0 mg/kg) showed smaller increases in the striatum, but not in the rest of the brain. Dihydroxyphenylacetic acid (DOPAC), another DA metabolite not affected by haloperidol, increased in the striatum and decreased in the rest of the brain of clozapine-injected rats. 5-Hydroxyindoleacetic acid, the predominant metabolite of serotonin, increased with haloperidol and decreased with clozapine. A high dose of haloperidol (5.0 mg/kg) increased DA and 5-HT, while an equivalent does of clozapine (10.0 mg/kg) decreased levels in the rest of the brain. The effects of both drugs on the HVA/5-HIAA and DOPAC/5-HIAA ratios were also different., Conclusions: The differing activities of the two drugs at DA and serotonin receptors implies an important role for serotonin in treatment-resistant schizophrenia and a lower incidence of EPS.

In view of a possible role of presynaptic serotonin (5-hydroxytryptamine, 5-HT) receptors in the precipitation of extrapyramidal side effects (EPS), the present study was designed to investigate the neurochemical effects of a selective 5-HT1A ligand, 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT) in rats following single (5 mg/kg) and repeated (two-times a day for 9 days at dosage of 5mg/kg) haloperidol administration. Haloperidol plus 8-OH-DPAT injected animals exhibited a decrease in dopamine (DA) and an increase in DA metabolite homovanillic acid (HVA) levels in the striatum and rest of the brain. The two groups of animals exhibited comparable levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum and rest of the brain. Animals injected with haloperidol and killed 24 hrs after the last injection of haloperidol exhibited higher DA and HVA levels in the striatum but not in the rest of the brain. Conversely, dihydroxyphenylacetic acid (DOPAC), the other metabolite of DA, decreased in the rest of the brain. 5-HIAA concentrations increased in the striatum but not in the rest of the brain. Administration of 8-OH-DPAT significantly decreased 5-HT and 5-HIAA levels in the rest of brain and did not alter 5-HIAA in the striatum of repeated saline injected rats. Conversely, same dose of 8-OH-DPAT injected to repeatedly haloperidol injected animals did not decrease 5-HT and 5-HIAA concentrations in the rest of the brain but decreased 5-HIAA levels in the striatum. No effect of 8-OH-DPAT injections occurred on striatal or rest of the brain DA metabolism in repeatedly saline injected animals except that DOPAC decreased in the striatum of both groups. The results are discussed in the context of a role of somatodendritic 5-HT1A receptors in the regulation of DA metabolism following single and repeated administration of haloperidol. It is suggested that an increase in the responsiveness of these receptors may be involved in the precipitation of EPS observed in patients on haloperidol therapy.