2D NMR Studies on the Benzodiheteropine and its Cycloaddition Products

苯并硫氮杂卓是一类具有镇静作用的合成药物，对精神病，心脏病及高血压等疾病有一定疗效。为了深入探讨其结构与药效关系，应用１Ｈ１ＨＣＯＳＹ，１３Ｃ１ＨＣＯＳＹ和ＮＯＥＳＹ等２ＤＮＭＲ技术对苯并硫氮杂卓１及其环加成产物２～５进行了研究，对其１Ｈ、１３ＣＮＭＲ化学位移进行了指定，并分析讨论了化合物１～５的结构特征及苯并硫氮七元杂环呈船式构象的特点，各相关质子间的偶合常数也与讨论结果相符     

How much do the public sector and the private sector contribute to biopharmaceutical R&D?

When examining the prices of new medicines, the question of how much the private and public sectors have contributed to their R&D is often raised. Contributions can be assessed in terms of the investment, authorship of publications, marketing authorizations and intellectual property rights associated with biopharmaceutical R&D. This review of the empirical evidence underlines the complementary and interwoven nature of the private and public sectors in supporting biopharmaceutical R&D. Both sectors invest in and contribute to biopharmaceutical R&D, with the public sector predominantly focusing on basic research and the private sector mainly targeting medicine discovery and development. Public-sector investment generates additional private-sector investment.     

Imaging the high-affinity state of the dopamine D2 receptor in vivo: Fact or fiction?

Positron Emission Tomography (PET) has been used for more than three decades to image and quantify dopamine D2 receptors (D2R) in vivo with antagonist radioligands but in the recent years agonist radioligands have also been employed. In vitro competition studies have demonstrated that agonists bind to both a high and a low-affinity state of the D2Rs, of which the high affinity state reflects receptors that are coupled to G-proteins and the low-affinity state reflects receptors uncoupled from G-proteins. In contrast, antagonists bind with uniform affinity to the total pool of receptors. Results of these studies led to the proposal that D2Rs exist in high and low-affinity states for agonists in vivo and sparked the development and use of agonist radioligands for PET imaging with the primary purpose of measuring the proportion of receptors in the high-affinity (activating) state. Although several lines of research support the presence of high and low-affinity states of D2Rs and their detection by in vivo imaging paradigms, a growing body of controversial data has now called this into question. These include both in vivo and ex vivo studies of anesthesia effects, rodent models with increased proportions of high-affinity state D2Rs as well as the molecular evidence for stable receptor-G-protein complexes. In this commentary we review these data and discuss the evidence for the in vivo existence of D2Rs configured in high and low-affinity states and whether or not the high-affinity state of the D2R can, in fact, be imaged in vivo with agonist radioligands.     

Virtual pharmaceutical R&D: a strategy for the millennium?

`To be a success a virtual company must add value'     

Evaluating the preceptor–preceptee relationship among Pharm D students at the King Saud University School of Pharmacy

Objective

To evaluate preceptee satisfaction concerning preceptorship and the preceptor–preceptee relationship among pharmacy students.

Comparing the influence of dopamine D₂ polymorphisms and plasma drug concentrations on the clinical response to risperidone

Although several studies have reported that dopamine D? receptor (DRD2) polymorphisms affect the therapeutic efficacy of antipsychotics, other studies have suggested that the plasma drug concentration is related to the clinical response. Currently, there are no definitive data regarding which factor has greater clinical significance. Sixty patients with acute exacerbations of schizophrenia received 6 mg/d of risperidone for 4 weeks. Clinical evaluations using the Brief Psychiatric Rating Scale and the Udvalg for Klinicke Unders?gelser Side Effect Rating Scale were performed before and after administration of risperidone. TaqI A and -141C Ins/Del polymorphisms were determined, and the plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. The TaqI A polymorphism had no effect on therapeutic efficacy, but the -141C Ins/Del polymorphism was associated with an improvement in positive symptoms. In addition, the plasma concentration of the active moiety (risperidone plus 9-hydroxyrisperidone) correlated with the improvement in the total Brief Psychiatric Rating Scale score as well as with positive symptoms. Although there were no associations between DRD2 polymorphisms and psychic adverse effects, the plasma drug concentration was associated with psychic adverse effects. These findings suggest that DRD2 polymorphisms are associated with the therapeutic effects of risperidone as they relate to positive symptoms and that plasma drug concentrations are associated with overall symptoms as well as excitement and cognitive symptoms. Both the genotyping of DRD2 and the monitoring of plasma drug concentrations may be useful for improving clinically dominant symptoms. Further work involving replication in a larger sample is required to support our findings.     

Selective attenuation of the antinociceptive effects of μ opioids by the putative dopamine D3 agonist 7-OH-DPAT

Rationale: The purpose of the present investigation was to evaluate the effects of the D₃ agonist (±)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), various dopamine (DA) agonists and DA antagonists on the antinociceptive effects of μ opioids. Methods: Antinociception was assessed using a warm-water tail-withdrawal procedure in rats. Results: The μ opioids morphine (0.3–10 mg/kg) and dezocine (0.03–3.0 mg/kg) produced dose-dependent increases in antinociception with maximal effects obtained at the higher doses tested. Pretreatment with the putative D₃ agonist 7-OH-DPAT (1.0–10 mg/kg) produced a dose-dependent attenuation of the antinociceptive effects of morphine and dezocine. At the highest dose of 7-OH-DPAT tested, the morphine dose-effect curve was shifted rightward by approximately 1.5 log units and the dezocine curve by greater than 2.3 log units. The (+)-isomer of 7-OH-DPAT (1.0 and 3.0 mg/kg) also shifted the morphine dose-effect curve to the right in a dose-dependent manner. The DA D₃/D₂ agonist (−)-quinpirole (0.1–10 mg/kg) attenuated the effects of morphine, but these effects were small in magnitude, not dose-dependent and observed only under a limited set of conditions. The DA D₂/D₃ antagonist spiperone failed to alter the morphine dose-effect curve, but reversed the effects of 7-OH-DPAT on morphine antinociception. Pretreatment with the DA D₁ agonist (±)-SKF38393 (1.0 and 10 mg/kg) and the D₁ antagonist (+)-SCH23390 (0.1 and 1.0 mg/kg) failed to alter the morphine dose-effect curve. Conclusion: The finding that 7-OH-DPAT markedly attenuated the effects of morphine and that these effects were reversed with spiperone suggests that activity at the D₃, and possibly the D₂, receptor can modulate μ agonist-induced antinociception. Received: 30 June 1998/Final version: 12 January 1999     

Selective dopamine antagonist pretreatment on the antiparkinsonian effects of benzazepine D1 dopamine agonists in rodent and primate models of parkinson's disease — the differential effects of D1 dopamine antagonists in the primate

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, pretreatment with the D₁ DA antagonists, SCH 23390 (7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3-benzazepine) and A66359 (1-[2-bromo-4, 5-dimethoxybenzyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4 tetrahydroisoquinoline), but not the D₂ DA antagonist raclopride inhibited the contralateral circling induced by the benzazepine D₁ DA agonists SKF 38393 (7-H, 3-H analogue of SCH 23390), SKF 80723 (7-H, 3-H, 6-Br analogue) and SKF 83959 (7-H, 6-Cl, 3-CH₃ analogue). In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of SKF 80723 and SKF 83959 increased locomotor activity and reversed the motor disability. Grooming and oral activities were also increased. Pretreatment with SCH 23390 and A66359 inhibited all the behavioural changes induced by both D₁ DA agonists. In general, higher doses of A66359 and more especially SCH 23390 were needed to inhibit SKF 83959 and SKF 80723 induced increases in oral activity and grooming than locomotor activity. Raclopride pretreatment did not affect SKF 83959 and SKF 80723 induced oral activity and grooming, though it reduced the duration of the locomotor changes induced by the D₁ DA agonists. These findings demonstrate that the behavioural effects of benzazepine D₁ DA agonists in the 6-OHDA lesioned rat and MPTP-treated marmoset are mediated by D₁ DA receptor sites, although in the primate, stimulation of D₂ DA receptors by endogenous DA may be necessary in facilitating the antiparkinsonian effects of D₁ DA agonists. The differential sensitivities of locomotor/motor disability and oral/grooming behaviours to antagonism by D₁ DA antagonists may indicate the involvement of multiple D₁ DA receptor subtypes in mediating benzazepine D₁ DA agonist induced behaviours in the MPTP-treated marmoset.     

Polymorphisms in CYP2D6 duplication-negative individuals with the ultrarapid metabolizer phenotype: a role for the CYP2D6*35 allele in ultrarapid metabolism?

Ultrarapid drug metabolism mediated by CYP2D6 is associated with inheritance of alleles with duplicated or amplified functional CYP2D6 genes. However, genotyping for duplicated CYP2D6 alleles only explains a fraction (10-30%) of the ultrarapid metabolizer phenotypes observed in Caucasian populations. Using a sample of CYP2D6 duplication-negative ultrarapid metabolizer subjects and selected control subjects with extensive metabolism, we examined parts of the CYP2D7 pseudogene, and the promoter region and 5'-coding sequence of CYP2D6 for polymorphisms possibly associated with the ultrarapid metabolizer phenotype. In an initial screening of 17 subjects (13 ultrarapid metabolizers and four extensive metabolizers), we identified three DNA variants in the 5'-end of the CYP2D7 pseudogene and 29 variants in the 5'-end of the CYP2D6 gene. Five variants were then selected for examination in a larger sample of subjects having the ultrarapid metabolizer (n = 27) or extensive metabolizer phenotype (n = 77). Subsequent statistical analyses of allele, genotype and estimated haplotype distributions showed that the 31A allele of the 31G > A (Val(II)Met) polymorphism was significantly more frequent in ultrarapid metabolizer subjects than in extensive metabolizer subjects (P = 0.04). Also, estimation of haplotype frequencies suggested that one of the haplotypes with the 31A variant was significantly more frequent among the ultrarapid metabolizers compared with the extensive metabolizers (P = 0.03). The average metabolic ratio was significantly lower in subjects possessing the 31A allele compared with subjects homozygous for the 31G allele (P = 0.02). We also observed a nonsignificant over-representation of the G-allele of a - 1584 C > G promoter polymorphism in the ultrarapid metabolizer group. Since our results are based on a relatively low number of subjects, further studies on larger samples and functional analyses of the polymorphisms detected are necessary to determine the role of the 31G > A and - 1584C > 6 variants in CYP2D6 duplication-negative ultrarapid metabolizer subjects.     

Cathepsin D overexpression in the nervous system rescues lethality and Aβ42 accumulation of cathepsin D systemic knockout in vivo

The lysosome is responsible for protein and organelle degradation and homeostasis and the cathepsins play a key role in maintaining protein quality control. Cathepsin D(CTSD), is one such lysosomal protease, which when deficient in humans lead to neurolipofuscinosis(NCL) and is important in removing toxic protein aggregates. Prior studies demonstrated that CTSD germ-line knockout-CtsdKO(CDKO) resulted in accumulation of protein aggregates, decreased proteasomal activities, and postnatal lethalit...     

Involvement of the dopamine D1 receptor system in the anxiolytic effect of cedrol in the elevated plus maze and light–dark box tests

Cedrol, mainly derived from Juniperus virginiana L. essential oil, has been demonstrated the anxiolytic effect, although its mechanism of action is still not fully established. In the present study, male ICR mice were submitted to the elevated plus maze (EPM) and light–dark box (LDB) tests to investigate the putative mechanism of anxiolytic effect. WAY100635 (5-HT_1A receptor antagonist), flumazenil (benzodiazepine receptor antagonist), SCH23390 (dopamine D₁ receptor antagonist) or sulpiride (dopamine D₂/D₃ receptor antagonist) were used in the behavioral experiment to determine the mechanism of action of cedrol. Subsequently, the monoamine neurotransmitter levels were evaluated after behavioral tests. The data suggest that no significant effect in behavioral parameters were observed after sole intraperitoneal (i.p.) injection of antagonists compared to saline group. The anxiolytic effect of cedrol in behavioral procedures was blocked by either WAY100635 or flumazenil. The anxiolytic effect of cedrol (1200 mg/kg) was effectively antagonized by SCH23390 (0.125 mg/kg). Furthermore, cedrol decreased the DA and NE levels in hippocampus, striatum and hypothalamus. The present findings suggest that the dopaminergic system (D₁ receptor) rather than serotoninergic or GABAergic system may potentially be involved in the modulation of cedrol-induced anxiolytic-like behaviors in mice.     

Daldinans D‒G,new isoindolinone antioxidants isolated from the ascomycete Daldinia concentrica

Journal of Natural Medicines - Four new isoindolinone derivatives, daldinans D?G (3?6), together with two known compounds, daldinans A and B (1 and 2), were isolated from the stroma of...