Discovery of Potent Agonists for the Predominant Variant of the Orphan MAS-Related G Protein-Coupled Receptor X4 (MRGPRX4).

The MAS-related G protein-coupled receptor X4 (MRGPRX4) is poorly investigated. MRGPRX4 has been proposed to be involved in pain transmission, itch, inflammation, wound healing, and cancer. However, so far only a few moderately potent, nonselective MRGPRX4 agonists have been described, most of which appear to preferably activate the minor receptor variant MRGPRX4-83L but not the main variant 83S.

Antiplatelet Effects of Selected Xanthine-Based Adenosine A and A Receptor Antagonists Determined in Rat Blood.

The platelet aggregation inhibitory activity of selected xanthine-based adenosine A and A receptor antagonists was investigated, and attempts were made to explain the observed effects. The selective A receptor antagonist PSB-603 and the A receptor antagonist TB-42 inhibited platelet aggregation induced by collagen or ADP. In addition to adenosine receptor blockade, the compounds were found to act as moderately potent non-selective inhibitors of phosphodiesterases (PDEs).

A Adenosine Receptor Antagonists with Picomolar Potency.

The A adenosine receptor (AAR) was proposed as a novel target for the (immuno)therapy of cancer since AAR blockade results in antiproliferative, antiangiogenic, antimetastatic, and immunostimulatory effects. In this study, we explored the structure-activity relationships of xanthin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established, which facilitated the synthesis of the target compounds.

Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity.

Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1- ]purinediones with the aim to obtain multi-target drugs that block human A and A adenosine receptors (ARs) and monoaminoxidase B (MAO-B).

2-Amino[1,2,4]triazolo[1,5-c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure-Activity Relationships of Potent Adenosine Receptor Antagonists.

2-Amino[1,2,4]triazolo[1,5-c]quinazolines were identified as potent adenosine receptor (AR) antagonists. Synthetic strategies were devised to gain access to a broad range of derivatives including novel polyheterocyclic compounds. Potent and selective A AR antagonists were discovered, including 3,5-diphenyl[1,2,4]triazolo[4,3-c]quinazoline (17, K human A AR 1.

8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors.

Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases.

Does combined antioxidant vitamin supplementation blunt repeated bout effect?

We investigated the effect of antioxidant supplementation on markers of muscle damage, antioxidant status, and delayed onset of muscle soreness (DOMS) after repeated downhill runs. Moderately-trained males (n=22) were randomly assigned to a supplement (S) or placebo (P) group. Capsules (vitamin C:1 000 mg/d; vitamin E: 400 IU/d) were ingested daily for 2 weeks.

8-Benzyltetrahydropyrazino[2,1-f]purinediones: water-soluble tricyclic xanthine derivatives as multitarget drugs for neurodegenerative diseases.

8-Benzyl-substituted tetrahydropyrazino[2,1-f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual-target-directed A1 /A2A adenosine receptor antagonists were identified.

1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases.

Adenosine receptors and monoamine oxidases are drug targets for neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In the present study we prepared a library of 55 mostly novel tetrahydropyrimido[2,1-f]purinediones with various substituents in the 1- and 3-position (1,3-dimethyl, 1,3-diethyl, 1,3-dipropyl, 1-methyl-3-propargyl) and broad variation in the 9-position. A synthetic strategy to obtain 3-propargyl-substituted tetrahydropyrimido[2,1-f]purinedione derivatives was developed.

Assessing stress in disability: developing and piloting the Disability Related Stress Scale.

Background: Stress negatively influences health, but few scales capture unique stressors encountered by people with physical disability.

Objective/hypothesis: Conduct a pilot study to develop and evaluate the factor structure of a stress measure targeting unique stressors facing people with physical limitations due to impaired movement of the upper and lower extremities.

Methods: Development of the Disability Related Stress Scale (DRSS) included: (1) obtaining input regarding content and items from focus groups and outside experts and (2) piloting the instrument.

Changes in depressive symptoms and impact on treatment course among hepatitis C patients undergoing interferon-α and ribavirin therapy: a prospective evaluation.

Objectives: Accounting for severity of depressive symptoms at baseline (pretreatment), this study describes (i) depressive symptom change over the course of antiviral treatment among patients with hepatitis C virus (HCV), and (ii) the relationship of such symptom change to treatment duration and response.

Methods: Depressive symptoms, measured with the Beck Depression Inventory (BDI), were examined prospectively among 129 HCV patients (95% male) who endorsed minimal (n=91), mild (n=28), or moderate depressive symptoms (n=10) prior to commencement of antiviral therapy. Assessments were obtained at baseline, 2 weeks, 4 weeks, and thereafter at 4-week intervals until treatment was discontinued or completed.

Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists.

Rationale: Adenosine A(2A) antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone.

Objective: The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists.

Effect of the adenosine A2A receptor antagonist MSX-3 on motivational disruptions of maternal behavior induced by dopamine antagonism in the early postpartum rat.

Rationale: Mesolimbic dopamine (DA), particularly in the nucleus accumbens, importantly regulates activational aspects of maternal responsiveness. DA antagonism and accumbens DA depletions interfere with early postpartum maternal motivation by selectively affecting most forms of active maternal behaviors, while leaving nursing behavior relatively intact. Considerable evidence indicates that there is a functional interaction between DA D2 and adenosine A(2A) receptors in striatal areas, including the nucleus accumbens.

Interactions between adenosine and dopamine receptor antagonists with different selectivity profiles: Effects on locomotor activity.

Forebrain dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation. Adenosine A(2A) antagonists reverse many of the behavioral effects of DA antagonists, and A(2A) receptors are co-localized with D(2) receptors on striatal medium spiny neurons. The present work was undertaken to determine if the ability of an A(2A) antagonist, a non-selective adenosine antagonist, or an A(1) antagonist to reverse the locomotor effects of DA blockade in rats differed depending upon whether D(1) or D(2) family receptors were being antagonized.

Nucleus accumbens and effort-related functions: behavioral and neural markers of the interactions between adenosine A2A and dopamine D2 receptors.

Nucleus accumbens dopamine (DA) is a critical component of the brain circuitry regulating work output in reinforcement-seeking behavior and effort-related choice behavior. Moreover, there is evidence of an interaction between DA D(2) and adenosine A(2A) receptor function. Systemic administration of adenosine A(2A) antagonists reverses the effects of D(2) antagonists on tasks that assess effort related choice.

Oral tremor induced by the muscarinic agonist pilocarpine is suppressed by the adenosine A2A antagonists MSX-3 and SCH58261, but not the adenosine A1 antagonist DPCPX.

Tremulous jaw movements in rats, which can be induced by dopamine (DA) antagonists, DA depletion, and cholinomimetics, have served as a useful model for studies of tremor. Although adenosine A(2A) antagonists can reduce the tremulous jaw movements induced by DA antagonists and DA depletion, there are conflicting reports about the interaction between adenosine antagonists and cholinomimetic drugs. The present studies investigated the ability of adenosine antagonists to reverse the tremorogenic effect of the muscarinic agonist pilocarpine.

Caffeine and an adenosine A(2A) receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life.

Seizures early in life cause long-term behavioral modifications, namely long-term memory deficits in experimental animals. Since caffeine and adenosine A(2A) receptor (A(2A)R) antagonists prevent memory deficits in adult animals, we now investigated if they also prevented the long-term memory deficits caused by a convulsive period early in life. Administration of kainate (KA, 2 mg/kg) to 7-days-old (P7) rats caused a single period of self-extinguishable convulsions which lead to a poorer memory performance in the Y-maze only when rats were older than 90 days, without modification of locomotion or anxiety-like behavior in the elevated-plus maze.

The adenosine A2A antagonist MSX-3 reverses the effects of the dopamine antagonist haloperidol on effort-related decision making in a T-maze cost/benefit procedure.

Rationale: Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Research involving choice tasks has shown that rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements and instead select less effortful food-seeking behaviors.

Objective: Previous work showed that adenosine A(2A) antagonism can reverse the effects of the DA antagonist haloperidol in an operant task that assesses effort-related choice.

The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists.

Rationale: Brain dopamine (DA) participates in the modulation of instrumental behavior, including aspects of behavioral activation and effort-related choice behavior. Rats with impaired DA transmission reallocate their behavior away from food-seeking behaviors that have high response requirements, and instead select less effortful alternatives. Although accumbens DA is considered a critical component of the brain circuitry regulating effort-related choice behavior, emerging evidence demonstrates a role for adenosine A(2A) receptors.

Prevalence, type, disclosure, and severity of adverse life events in college students.

Objective: Some information on the prevalence of adverse life experiences is available for the general population and college students, but the extent, nature, and severity of these events is unclear.

Participants: The authors recruited undergraduate college students (N = 6,053) from diverse academic settings (public and private schools) and geographic locations.

Methods: They examined the prevalence, nature, severity, and disclosure of adverse events, in addition to reports of posttraumatic stress disorder (PTSD) symptomatology within the sample.

Dopamine/adenosine interactions related to locomotion and tremor in animal models: possible relevance to parkinsonism.

Adenosine A(2A) antagonists can exert antiparkinsonian effects in animal models. Recent experiments studied the ability of MSX-3 (an adenosine A(2A) antagonist) to reverse the locomotor suppression and tremor produced by dopamine antagonists in rats. MSX-3 reversed haloperidol-induced suppression of locomotion, and reduced the tremulous jaw movements induced by haloperidol, pimozide, and reserpine.

Tremorolytic effects of adenosine A2A antagonists: implications for parkinsonism.

Drug-induced tremulous jaw movements in rats have been used as a model of parkinsonian tremor. Because adenosine A2A antagonists have antiparkinsonian effects, the present experiments were conducted to study the ability of adenosine A2A antagonism to reverse the tremulous jaw movements produced by the antipsychotic drugs pimozide, haloperidol and reserpine. In one group of studies, rats received daily injections of the dopamine antagonist pimozide, and on day 8 they received injections of pimozide plus various doses of the A2A antagonists KW 6002 or MSX-3.

Synthesis and properties of a new water-soluble prodrug of the adenosine A 2A receptor antagonist MSX-2.

The compound L-valine-3-{8-[(E)-2-[3-methoxyphenyl)ethenyl]-7-methyl-1-propargylxanthine-3-yl}propyl ester hydrochloride (MSX-4) was synthesized as an amino acid ester prodrug of the adenosine A2A receptor antagonist MSX-2. It was found to be stable in artificial gastric acid, but readily cleaved by pig liver esterase.

Expressive writing and post-traumatic stress disorder: effects on trauma symptoms, mood states, and cortisol reactivity.

Objectives: This study investigates the boundary conditions (feasibility, safety, and efficacy) of an expressive writing intervention for individuals with post-traumatic stress disorder [PTSD].

Design: Randomized trial with baseline and 3-month follow-up measures of PTSD severity and symptoms, mood states, post-traumatic growth, and (post-only) cortisol reactivity to trauma-related stress.

Methods: Volunteers with a verified diagnosis of PTSD (N=25) were randomly assigned to an experimental group (writing about their traumatic experience) or control group (writing about time management).