Biomedical subjects

Y Landry

Publications and source records attributed to Y Landry.

114 records · Page 7Linked to original sources

PubMedDate not supplied

Structure-activity studies of bradykinin analogues on rat mast cell histamine release.

Bradykinin (BK), kallidin (KD), and various analogues induced histamine release from rat mast cells. The results obtained with substituted analogues of BK indicated that: 1) the presence of both Arg residues at position 1 and 9 of kinins was favorable to confer histamine-releasing activity, 2) acetylation of the N-terminal amino acid residue led to a drastic reduction of this activity, 3) addition of a D-Arg residue at the N-terminus reduced their activity, as well as trans-4-hydroxyproline (Hyp) substitutions at position 2 or 3,4) D-Arg0 addition and Hyp3 substitution were synergistic in lowering activity, and 5) D-Phe7 substitution led to enhanced histamine-releasing activity.

Amino Acid Sequence↗

PubMedDate not supplied

Inverse agonism at heptahelical receptors: concept, experimental approach and therapeutic potential.

Inverse agonists (negative antagonists) are ligands that stabilize the inactive conformation (R) of receptors according to the two-state receptor model. The active conformation (R*) of heptahelical receptors, i.e. G protein-coupled receptors, has high affinity for G proteins. According to ternary complex models of receptor activation, the R*G complex is in equilibrium with R + G, with spontaneous activity in the absence of agonist. Inverse agonists, having a higher affinity for R, shift R*G towards R + G, decreasing the spontaneous activity of receptors. Agonists have the opposite effect, with a higher affinity for R*. Neutral antagonists have the same affinity for R and R* and compete for both agonists and inverse agonists. Inverse agonists have been recently proposed for a variety of heptahelical receptors. Methods to detect inverse agonists among antagonists are based on the determination of ligand affinity at R and R* with binding experiments, and on the modulation of G protein activity (GTP binding and hydrolysis) or of effector activity. Receptor inverse agonists, but also G protein antagonists and GTPase inhibitors, decrease spontaneous G protein activity corresponding to R*G. Receptor agonists, G protein agonists and GTPase inhibitors increase effector basal activity, but receptor inverse agonists decrease it. The therapeutic potential of inverse agonists is proposed in human diseases ascribed to constitutively active mutant receptors and may be extended to diseases related to wild-type receptor over-expression leading to the increase of R*. Some of the therapeutic effects of presently used receptor antagonists may be related to their inverse agonist properties. Inverse agonists lead to receptor upregulation, offering new approaches to tolerance and dependence to drugs.

Animals↗

PubMedDate not supplied

M2-muscarinic receptors: how does ligand binding affinity relate to intrinsic activity?

In this study we looked for evidence regarding a correlation between M2-muscarinic receptor binding affinity and ligand intrinsic activity. Guanine nucleotide-binding protein-coupled receptors have been shown to exist in both a high affinity and a low affinity, agonist state. The agonist [3H]Oxotremorine-M, was used to determine the affinity of compounds for the high affinity state and the antagonist, [3H]N-methylscopolamine, plus GppNHp, was used to determine the affinity for the low agonist state. The magnitude of the difference in the affinity a compound has for the high versus the low agonist state of the receptor has been related to the intrinsic activity of the compound. NMS/Oxo-M ratios were established for muscarinic agonists, partial agonists and antagonists. NMS/Oxo-M ratios varied from 1695 for the agonist carbachol to 1.9 for the antagonist AFDX-166 with intermediate values for the partial agonists oxotremorine-M, pilocarpine and RS86 (233, 36 and 17 respectively). Intrinsic activity was assessed by receptor-mediated Gi-protein GTPase activity. Indeed, a close correlation (r=0.92) was found between the NMS/Oxo-M ratios of the ligands on the one hand, and their ability to activate the M2-receptor coupled Gi-protein on the other.

Animals↗

PubMedDate not supplied

Dual effect of phorbol ester on serosal mast cell exocytosis: interactions between ionic gradients and protein kinase C.

The phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA) induces a slow secretion of histamine from rat peritoneal mast cells. This secretion is dose-dependent from 0.3 to 10 ng/ml. Higher doses are less efficient. The absence of magnesium and/or potassium increases mast cell exocytosis induced by TPA. In the absence of both potassium and magnesium, extracellular calcium concentrations above 3 X 10(-5)M inhibit the effect of TPA. The sensitivity of mast cells to other inducers of histamine release is modified by pretreatment with TPA. The ionophore A23187-induced secretion is potentiated or inhibited according to the dose of TPA and the concentration of extracellular calcium. The absence of potassium prevents the potentiating effect of TPA. The secretory effect of compound 48/80 is decreased by pretreatment of mast cells with TPA. This effect is more potent in the absence of potassium. These results suggest that the activation of protein kinase C acts as a bidirectional regulator of mast cell exocytosis and is modulated by transmembrane gradients of monovalent and divalent ions. Its inhibitory effects might be favoured by the highest levels of cytosolic calcium and could be related to the inhibition of a guanine nucleotide regulatory protein involved in the transduction of the receptor signal to phosphatidylinositides turnover.

Animals↗

PubMedDate not supplied

Pharmacological inhibition of calmodulin-sensitive phosphodiesterases.

Two cyclic nucleotide phosphodiesterases sensitive to calmodulin were partially purified from bovine brain and bovine aorta. The enzyme from bovine brain exhibited the properties of the "high Km phosphodiesterase", with a higher Km for cyclic AMP than for cyclic GMP. The enzyme from bovine aorta hydrolyzed both cyclic AMP and cyclic GMP with similar kinetics. The hydrolysis of cyclic AMP by the brain enzyme was selectively inhibited by papaverine and 2' deoxy cyclic AMP. The hydrolysis of cyclic GMP by this enzyme was selectively inhibited by cyclic IMP, 2' deoxy cyclic GMP, 1-methyl-3-isobutyl-xanthine, ICI 74917 and M & B 22948. All these inhibitors were identically potent on the hydrolysis of both substrates by the aorta enzyme. Ro-20 1724, an imidazolidinone, and ZK 62711, a pyrrolidone, two compounds known to be potent inhibitors of cyclic AMP phosphodiesterase insensitive to calmodulin, were inefficient inhibitors of both calmodulin-sensitive phosphodiesterases.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMedDate not supplied

[Mechanisms of asthma. II. Potential pharmacological targets].

The pharmacological modifications of the airways contraction and of the secretion of mediators of anaphylaxis appear as the main way to therapeutic control of asthma. Calcium antagonists which inhibit calcium influx in the pulmonary smooth muscle have been proposed as antiasthmatic drugs. The pharmacological use of inhibitors of calmodulin, the intracellular target of calcium, requires the development of specific calmodulin inhibitors. The secretion of the mediators of anaphylaxis involves modifications of membranous phospholipids metabolism. The cytoskeleton might control the exocytosis of stored mediators. The multiplicity of putative mediators, of cellular systems and of various interrelationships between mediators of anaphylaxis and neuromediators, suggest multiple potential pharmacological targets in asthma.

Anaphylaxis↗