Sphingosine-1-phosphate (S1P) receptor agonists are novel immunosuppressive agents. The selectivity of S1P1 against S1P3 is strongly correlated with lymphocyte sequestration and minimum acute toxicity and bradycardia. This study describes molecular modeling, site-directed mutagenesis, and affinity studies exploring the molecular basis for selectivity between S1P1 and S1P3 receptors. Computation...

OBJECTIVES To determine whether, in stable patients with chronic obstructive pulmonary disease, administration of theophylline in combination with short-acting or long-acting inhaled beta2-agonists is more efficacious than is a placebo or each of these drugs used in isolation. METHODS A systematic review and meta-analysis were carried out. All randomized and double-blind clinical trials found...

Spontaneous eye blink rate was assessed in cynomolgus monkeys treated intramuscularly with the high-efficacy dopamine (DA) agonists, (-)-apomorphine, naxagolide, PD 128,907, 2-(N-phenylethyl-N-propyl)amino-5-hydroxytetralin (+/-)-PPHT, quinpirole, SKF 81297 and SKF 82958; the low-efficacy DA agonists, (-)-3-PPP, roxindole, SDZ 208-912, SKF 75670 and terguride; and the indirect DA agonists, d-am...

This study examined the signal transduction correlates of mu opioid agonist efficacy in two systems: mu receptor-transfected mMOR-CHO cell and rat thalamic membranes. The potency and maximal stimulation of [35S]GTP gamma S binding by various agonists was measured in the presence of excess GDP and compared with receptor binding affinity under identical assay conditions. Results showed that the r...

BACKGROUND Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural...

CONTENTS 1. Introduction 230 2. Concepts of the functional role of striatal dOpaminergic activity 231 2.1. Introduction 231 2.2. The behavioural actions of dopamine in the striatum: unitary or diverse? 231 2.3. Regional differences in the striatal functions revealed by the actions of dopamine 232 2.4. The side to which the striatum's behavioural effects are referred 232 2.4.1. The traditional v...

In primates, CB(1) cannabinoid receptor agonists produce sedation and psychomotor slowing, in contrast to behavioral stimulation produced by high doses of dopamine receptor agonists. To investigate whether dopamine agonists attenuate the sedative effects of a cannabinoid agonist in monkeys, we compared the effects of D(1) or D(2) dopamine receptor agonists on spontaneous behavior in three to si...

Several potent and selective A2A adenosine receptor agonists are currently available. These compounds have a high affinity for the A2A receptor and a long duration of action. However, in situations where a short duration of action is desired, currently available A2A receptor agonists are less than ideal. From a series of recently synthesized A2A receptor agonists, two agonists (CVT-3146 and CVT...

TLRs sense components of microorganisms and are critical host mediators of inflammation during infection. Different TLR agonists can profoundly alter inflammatory effects of one another, and studies suggest that the sequence of exposure to TLR agonists may importantly impact on responses during infection. We tested the hypothesis that synergy, priming, and tolerance between TLR agonists follow ...

Research on Parkinson's disease has led to new hypotheses concerning the mechanisms of neurodegeneration and to the development of neuroprotective agents. Recent findings of impaired mitochondrial function, altered iron metabolism and increased lipid peroxidation in the substantia nigra of parkinsonian patients emphasize the significance of oxidative stress and free radical formation in the pat...