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We studied the role of receptors with high and low affinity for fMLF chemotaxic peptide in the generation of active oxygen species by umbilical cord blood granulocytes from newborns with normal neonatal period, born after normal or complicated gestation, in children with manifestations of bacterial infection born after complicated pregnancy, and in granulocytes of non-pregnant women with normal reproductive function. Granulocytes of children born after complicated pregnancy exhibited high reactivity in induction of respiratory burst in a wide range of fMLF concentrations. The presentation of receptors with high and low affinity on granulocytes during initiation of the respiratory burst differs in children born after complicated pregnancy and in healthy babies born after normal gestation. Presumably, the detected differences result from high expression of receptors with low affinity for fMLF and disorders or immaturity of mechanisms responsible for receptor inactivation.

This paper describes the studies of human recombinant basic fibroblast growth factor (rhFGF-2) for its effects on human osteoblast growth and phenotype expression. During a 24-h period of treatment, rhFGF-2 highly stimulated DNA synthesis in a dose-related fashion with a maximum stimulation of 150% for 1 ng/ml. On the other hand, rhFGF-2 decreases alkaline phosphatase activity, synthesis of type I collagen, and cumulative amount of osteocalcin. Moreover, rhFGF-2 provoked a threefold increase in the amount of intracellular cAMP. Scatchard plots show the presence of two classes of$[^{125}I$] rhFGF-2 receptors. This data suggests that rhFGF-2 which stimulate cell replication may act indirectly as an anabolic agent and stimulate some of the phenotypic expression markers.

We previously published a series of 8-methoxypirazolo[1,5-a]quinazolines (PQs) and their 4,5-dihydro derivatives (4,5(H)PQ) bearing the (hetero)arylalkylester group at position 3 as ligands at the γ-aminobutyric type A (GABAA) subtype receptor. Continuing the study in this field, we report here the design and synthesis of 3-(hetero)arylpyrazolo[1,5-a]quinazoline and 3-(hetero)aroylpyrazolo[1,5-a]quinazoline 8-methoxy substituted as interesting analogs of the above (hetero)arylalkylester, in which the shortening or the removal of the linker between the 3-(hetero)aryl ring and the PQ was performed. Only compounds that are able to inhibit radioligand binding by more than 80% at 10 μM have been selected for electrophysiological studies on recombinant α1β2γ2L GABAA receptors. Some compounds show a promising profile. For example, compounds 6a and 6b are able to modulate the GABAAR in an opposite manner, since 6b enhances and 6a reduces the variation of the chlorine current, suggesting that they act as a partial agonist and an inverse partial agonist, respectively. The most potent derivative was 3-(4-methoxyphenylcarbonyl)-8-methoxy-4,5-dihydropyrazolo[1,5-a] quinazoline 11d, which reaches a maximal activity at 1 μM (+54%), and it enhances the chlorine current at ≥0.01 μM. Finally, compound 6g, acting as a null modulator at α1β2γ2L, shows the ability to antagonize the full agonist diazepam and the potentiation of CGS 9895 on the new α+/β− ‘non-traditional’ benzodiazepine site.

Background: Many researchers have tried to correlate characteristics of ligand binding at G-protein–coupled receptor (GPCR) with ligand efficacy. The ternary complex model (TCM) is the traditional model for explaining the equilibrium of agonist-GPCR-G-protein interaction, and the effect of this interaction on agonist efficacy. However, no consistent correlation has been proven for various binding-efficacy data, so several extensions of the model have been proposed. These extensions are of descriptive value but their validity cannot be verified by binding-efficacy correlations. Therefore, we developed a novel approach to validate the TCM and its extensions. Methods: We simulated the predictions of the TCM for relationships within binding parameters. According to the TCM, an increase in the difference between high and low agonist affinities for a receptor (ie, greater KL/KH) should be accompanied by stability or an increase in the fraction of receptors bound to the agonist with high affinity (RH). To validate these predictions we performed ligand competition experiments for a set of ß2-adrenergic receptor (AR) agonists and analyzed the resulting binding data as well as data taken from relevant literature. Results: No smooth relationship exists between RH and KL/KH in our or others’ data, indicating the insufficiency of the TCM and its extensions. We introduce the allosteric modulators model as an alternative. Conclusions: To our knowledge, this is the first paper in which insufficiency of the TCM and its extensions based on binding data are shown, and the first in which the presence of allosteric modulators of ligand affinity is proven to be a necessity for explaining binding data at GPCRs.

In addition to their role as nutrients, nitrogen (N)-containing compounds are considered to be signaling molecules in plants. Plant development is modified by N-metabolites. Root architecture and root-to-shoot allocation are particularly sensitive to soil nitrate and these processes respond to nitrate via several mechanisms. Metabolic pathways are also influenced by N-compounds at several levels. The molecular mechanisms that exert this control are not yet understood but recent evidence suggests that N-effectors act by regulating gene expression as well as by exerting post-transcriptional and post-translational effects. Like the processes of nitrate and ammonium uptake and assimilation, organic acid synthesis and starch biosynthesis are modified by nitrate, glutamine and other products of N assimilation. In this chapter, we discuss the evidence for the role of nitrate and nitrogen metabolites, such as glutamine, as signals regulating plant morphology and metabolism.