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951.
In recent years, the concept of allosteric modulation of G-protein-coupled receptors (GPCRs) has matured and now represents an increasingly viable approach to drug discovery. This is evident in the fact that allosteric modulators have been reported for every class of GPCR, and several are currently in clinical trials with one drug example approved and launched. The allosteric approach has been highlighted for the potential of identifying highly selective compounds with a minimal propensity to produce adverse effect. While much has been written regarding the promises of this approach, important challenges, caveats, and pitfalls exist that are often overlooked. Therefore, a balanced overview of the field that describes both the promises and the challenges of discovering allosteric modulators of GPCRs as novel drugs is presented. 相似文献
952.
Meng CQ Ni L Worsencroft KJ Ye Z Weingarten MD Simpson JE Skudlarek JW Marino EM Suen KL Kunsch C Souder A Howard RB Sundell CL Wasserman MA Sikorski JA 《Journal of medicinal chemistry》2007,50(6):1304-1315
Starting from a simple chalcone template, structure-activity relationship (SAR) studies led to a series of carboxylated, heteroaryl-substituted chalcone derivatives as novel, potent inhibitors of vascular cell adhesion molecule-1 (VCAM-1) expression. Correlations between lipophilicity determined by calculated logP values and inhibitory efficacy were observed among structurally similar compounds of the series. Various substituents were found to be tolerated at several positions of the chalcone backbone as long as the compounds fell into the right range of lipophilicity. The chalcone alpha,beta-unsaturated ketone moiety seemed to be the pharmacophore required for inhibition of VCAM-1 expression. Compound 19 showed significant antiinflammatory effects in a mouse model of allergic inflammation, indicating that this series of compounds might have therapeutic value for human asthma and other inflammatory disorders. 相似文献
953.
954.
Rationale DBA/2 mice demonstrate poor prepulse inhibition (PPI) as is also observed in schizophrenic patients, and their PPI is improved
by antipsychotics. Thus, the DBA/2 mouse is increasingly used for testing of novel antipsychotics in PPI; however, the strain
has not been fully characterized for relevant variables affecting compound testing.
Objectives The objectives of this study were to compare four DBA/2 substrains, evaluate light- and dark-phase testing on startle, PPI,
and drug-induced improvement in PPI in DBA/2NCrl mice, test chamber lighting on startle and PPI in DBA/2NCrl mice and to evaluate
vehicles on baseline PPI in DBA/2NCrl mice.
Results DBA/2NCrl and DBA/2J mice were acceptable for PPI testing, while DBA/2NHsd mice had diminished startle reflexes. Startle responses
to the prepulses alone were observed in 46% of the DBA/2NTac mice. PPI and startle did not show diurnal variations or variations
due to chamber lighting. Olanzapine and aripiprazole showed better drug-induced improvements in PPI during the light phase.
The vehicle 25% (2-hydroxypropyl)-β-cyclodextrin variably improved PPI, an effect not observed with other vehicles.
Conclusions DBA/2NHsd and DBA/2NTac mice were unacceptable for PPI experiments. The finding of responses to the prepulses alone by DBA/2NTac
mice further indicates the advisability of routinely monitoring responses to prepulses alone. Unlike rats, DBA/2NCrl mice
did not have greater startle amplitudes during the dark phase. Compound efficacy was better during the light phase because
of poorer PPI in the vehicle group. Some vehicles may have unacceptable effects on PPI in DBA/2NCrl mice and may not be appropriate
for studies evaluating novel compounds. 相似文献
955.
Carotti A Piacentini G Marino B 《The Annals of thoracic surgery》2007,83(6):2262-2262; author reply 2263
956.
Dorothy G. Flood Matthew Choinski Michael J. Marino Maciej Gasior 《Psychopharmacology》2009,205(3):369-377
Rationale Lithium and several antiepileptic drugs have mood-stabilizing effects in bipolar disorder and schizophrenia. Both disorders
are characterized by deficits in prepulse inhibition (PPI) of the acoustic startle response.
Objectives Using the DBA/2 model of naturally low PPI, which is reliably increased by antipsychotics, five mood stabilizers in clinical
use were tested to determine whether they would also increase PPI in this model. All drugs were administered intraperitoneally
(i.p.) 30 min before testing.
Results Lithium chloride (30 mg/kg), topiramate (100 and 300 mg/kg), carbamazepine (30, 60, and 100 mg/kg), valproic acid (178 and
316 mg/kg), and lamotrigine (3, 10, and 30 mg/kg) increased percent PPI. The antiepileptic drugs carbamazepine, valproic acid,
and lamotrigine at high doses also decreased no-stimulus amplitudes and increased startle amplitudes. At high doses of carbamazepine,
valproic acid, and lamotrigine, increases in percent PPI were independent of the increases in startle amplitude.
Conclusions The demonstrated efficacy of five mood stabilizers in the DBA/2 model of naturally low PPI points to the translational value
of this model in predicting therapeutic activity in schizophrenia and bipolar disorder of compounds with diverse mechanisms
of action. 相似文献
957.
John A. Gruner Val R. Marcy Yin-Guo Lin Donna Bozyczko-Coyne Michael J. Marino Maciej Gasior 《Sleep》2009,32(11):1425-1438
Study Objective:
Rebound hypersomnolence (RHS: increased sleep following increased wake) is a limiting side-effect of many wake-promoting agents. In particular, RHS in the first few hours following wake appears to be associated with dopamine (DA)-releasing agents, e.g., amphetamine, but whether it can also be produced by DA transporter (DAT) inhibition alone is unknown. In these studies, DA-releasing and DAT-inhibiting agents and their interaction were systematically examined for their ability to increase wake and induce RHS.Design:
Chronically implanted rats were evaluated in a blinded, pseudo-randomized design.Participants:
237 rats were used in these studies with 1 week between repeat tests.Interventions:
Animals were habituated overnight and dosed the next day, 5 h after lights on, with test agents.Measurements and Results:
Sleep/wake activity and RHS were evaluated using EEG/EMG recording up to 22 h post dosing. In vitro dopamine release was evaluated in rat synaptosomes. At doses that produced equal increases in wake, DA-releasing (amphetamine, methamphetamine, phentermine) and several DAT-inhibiting agents (cocaine, bupropion, and methylphenidate) produced RHS during the first few hours after the onset of sleep recovery. However, other DAT-inhibiting agents (mazindol, nomifensine, GBR-12909, and GBR-12935) did not produce RHS. Combination treatment with amphetamine and nomifensine produced waking activity greater than the sum of their individual activities alone while ameliorating the amphetamine-like RHS. In rat synaptosomes, nomifensine reduced the potency of amphetamine to induce DA release ∼270-fold, potentially explaining its action in ameliorating amphetamine-induced RHS.Conclusions:
All DA releasing agents tested, and some DAT-inhibiting agents, produced RHS at equal wake-promoting doses. Thus amphetamine-like DA release appears sufficient for inducing RHS, but additional properties (pharmacologic and/or pharmacokinetic) evidently underlie RHS of other DAT inhibitors. Enhancing wake while mitigating RHS can be achieved by combining DAT-inhibiting and DA-releasing agents.Citation:
Gruner JA; Marcy VR; LinYG; Bozyczko-Coyne D; Marino MJ; Gasior M. The roles of dopamine transport inhibition and dopamine release facilitation in wake enhancement and rebound hypersomnolence induced by dopaminergic agents. SLEEP 2009;32(11):1425-1438. 相似文献958.
959.
Immunohistochemical study of bone sialoprotein and osteopontin in healthy and diseased root surfaces
BACKGROUND: Periodontal disease is marked by inflammation and damage to tooth-supporting tissues. In particular, damage occurs to factors present in cementum that are thought to have the ability to influence the regeneration of surrounding tissues. Bone sialoprotein and osteopontin are major non-collagenous proteins in mineralized connective tissues associated with precementoblast chemo-attraction, adhesion to the root surface, and cell differentiation. The purpose of this investigation was to determine whether the expression and distribution of bone sialoprotein and osteopontin on root surfaces affected by periodontitis are altered compared to healthy, non-diseased root surfaces. METHODS: Thirty healthy and 30 periodontitis-affected teeth were collected. Following fixation and demineralization, specimens were embedded in paraffin, sectioned, and exposed to antibodies against bone sialoprotein and osteopontin. Stained sections were assessed using light microscopy. RESULTS: Bone sialoprotein was not detected in the exposed cementum (absence of overlying periodontal ligament) of diseased teeth. In most areas where the periodontal ligament was intact, bone sialoprotein was detected for healthy and diseased teeth. For teeth reactive for bone sialoprotein, the matrix of the cementum just below the periodontal ligament was moderately stained. A similar immunoreactivity pattern for osteopontin was observed. CONCLUSIONS: The absence of bone sialoprotein and osteopontin staining along exposed cementum surfaces may be due to structural and compositional changes in matrix components associated with periodontal disease. This may influence the ability for regeneration and new connective tissue attachment onto previously diseased root surfaces. 相似文献
960.
Miranda C Prates LH Vieira Rde S Calvo MC 《The Journal of clinical pediatric dentistry》2006,31(1):35-40
The aims of this study were to evaluate the shear bond strength (SBS) off our adhesive systenms applied to primary dentin and enamel and verify, after SBS testing, the failure mode of the adhesive interface. Sixty extracted sound primary molars were selected and crowns were sectioned in a mesial-distal direction. Specimens were randomly assigned into two groups (adhesion to enamel and adhesion to dentin) and then subdivided into four subgroups according to the adhesive system (n=15). Scotchbond Multi-Purpose (SMP)--Single Bond (SB)--Clearfil SE Bond (and Adper Prompt L-Pop (APL)--SBS tests were performed and the obtained values were statistically analyzed using ANOVA and Tukey tests (p < 0.05). The failure mode analysis was performed with a Scanning Electron Microscope (XL-30, Philips). SBS mean values on enamel were [MPa (SD)]: SMP--2789 (749); SB--23.92 (8.8); CSB--24.36 (6.69), APL--25.96 (4.08); and on dentin: SMP--17.29 (4.25) SB--18.2 (8.74); CSB--16.13 (714); APL--6. 04 (3.35). The predominant failure mode was cohesive (primarily of the bonding agent). On enamel SBS was statistically similar for all four adhesives. On dentin SBS ofAPL was lower than the other tested adhesives. 相似文献