Biomedical subjects

B Chapelain

Publications and source records attributed to B Chapelain.

9 recordsLinked to original sources

PubMed2001

From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands.

Compound 1 obtained by random screening and displaying a micromolar activity on the mu opiate receptor was chosen as a starting point for optimization. Two complementary concepts of similarity were used for the design of analogues and compared. These are based, respectively, on a computer-aided comparison of pharmacophoric patterns and on topological similarity. The structure-activity relationships are discussed in light of both similarity concepts. Compound 40, an N-methyl-3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decyl)acetamide derivative, designed by combining the structure-activity relationships enlightened by each method, has a subnanomolar affinity for mu (h) receptor (IC(50) = 0.9 nM). It is a promising lead, allowing the design of a new series of analogues substituted at the N-3 of the spirocycle moiety.

Animals↗

PubMed2001

From hit to lead. Analyzing structure-profile relationships.

Two compounds, obtained by random screening, and displaying micromolar activities on the mu opiate receptor were used as starting points for optimization. In that work, the traditional concept of the activity of a compound (related to one or a few targets) was extended to the comprehensive pharmacological profile of that compound on more than 70 receptors, transporters, and channels relevant to a CNS-oriented project. Using the two complementary design strategies based on two similarity concepts described in the previous paper, we have obtained analogues with IC(50) values ranging between 0.9 nM and a few micromolar on the mu receptor and displaying qualitatively different profiles. We discuss here, both on a case-by-case basis and from a statistical standpoint, the pharmacological profiles in light of the two similarity concepts.

Brain↗

PubMed1998

Receptor binding profile of Otilonium bromide.

The interaction of Otilonium bromide (OB) with binding sites for 63 different receptors and ion channels in appropriate preparations has been investigated. Experiments were also performed in rat colon, the preferred tissue for OB 'in vivo' uptake after oral administration. Among the receptors investigated OB binds with sub microM affinity to muscarinic M1, M2, M4, M5 and PAF receptors and with microM affinity to the diltiazem binding site on L type Ca2+ channels. In the rat colon OB shows competitive interaction with the verapamil binding site on L type Ca2+ channels and with muscarinic M2 receptors with IC50 of 1020 and 1220 nM, respectively. These findings provide a molecular rationale to explain the spasmolytic action exerted by OB on intestinal smooth muscle. In particular, a combination of antimuscarinic and Ca2+ channel blocker properties seems to best account for the action of this compound.

Animals↗

PubMed1994

Up-regulation of [3H]-des-Arg10-kallidin binding to the bradykinin B1 receptor by interleukin-1 beta in isolated smooth muscle cells: correlation with B1 agonist-induced PGI2 production.

1. Binding of the specific bradykinin B1 receptor agonist, [3H]-des-Arg10-kallidin (-KD) was investigated in smooth muscle cells (SMC) isolated from rabbit mesenteric arteries (RMA). 2. [3H]-des-Arg10-KD specifically bound to interleukin-1 (IL-1)-treated RMA-SMC in a saturable fashion with an equilibrium dissociation constant (KD) of 0.3-0.5 nM. The number of binding sites per cell was 20,000-35,000. Kinins inhibited [3H]-des-Arg10-KD binding to RMA-SMC with an order of potency very similar to that observed in typical B1 specific bioassays: des-Arg9-bradykinin (BK) approximately KD >> BK. Furthermore, the B1 receptor antagonist [Leu8]des-Arg9-BK inhibited [3H]-des-Arg10-KD binding with an IC50 of 43 nM as expected for its effect at B1 receptors. The B2 receptor antagonists, NPC 567 and Hoe 140 only affected [3H]-des-Arg10-KD binding at very high concentrations (IC50 = 0.8 microM and IC50 > 10 microM, respectively). 3. Des-Arg9-BK (B1 agonist) and [Hyp3]Tyr(Me)8-BK (B2 agonist) did not induce prostacyclin (PGI2) production by RMA-SMC. Lipopolysaccharide (LPS) treatment of the cells did not affect the B1 agonist response whereas IL-1 beta treatment produced a 7 fold increase in des-Arg9-BK-stimulated PGI2 production. IL-1 beta also stimulated the response to B2 agonists. 4. Des-Arg9-BK-induced PGI2 secretion in IL-1-primed RMA-SMC was mediated by B1 receptors since it was inhibited by [Leu8]des-Arg9-BK (IC50 = 56-73 nM) but not by Hoe 140. High concentrations of NPC 567 (IC5o = 2.4 micro M) were required to inhibit PGI2 production induced by B1 agonists.5. IL- 1-treated RMA-SMC displayed a 5 fold increase in the number of B1 receptors without modification of the affinity constant, thus establishing a possible relationship between the receptor density and the IL-i-primed B1 response.6. LPS treatment of the cells induced a 4 fold increase in B1 receptor number without modifying PGI2 secretion. This observation suggests that IL-1 but not LPS, in addition to increase in the number of receptors, signals the cell to permit the coupling of B1 receptors to the PLA2/cyclo-oxygenase pathway.

Animals↗

PubMed1993

Different effects of interleukin-1 on reactivity of arterial vessels isolated from various vascular beds in the rabbit.

During septic shock, arterial smooth muscle is thought to be hyporeactive to vasoconstrictors. This hyporeactivity, however, seems to be different from one vascular bed to another. Interleukin-1 (IL-1), which is released during septic shock, might play a role in the different regional vascular responses to norepinephrine. Thus, the aim of the present study was to examine in vitro the effect of IL-1 on the response to norepinephrine of arteries isolated from different territories in the rabbit. Three types of responses were identified: IL-1 decreased NE-induced contraction by 54% in aorta, 42% in carotid artery, 54% in pulmonary artery, and 18% in renal artery; and IL-1 was devoid of significant effect in hepatic and mesenteric arteries; and IL-1 increased NE-induced contraction by 25% in femoral arteries. In conclusion, IL-1 might contribute to the regional blood flow abnormalities during septic shock.

Animals↗

PubMed1992

Interleukin-1 impairs both vascular contraction and relaxation in rabbit isolated aorta.

Incubation of rabbit aortic rings with interleukin-1 (100 U/ml) in vitro led to a depressed contractile response to norepinephrine, whether the endothelium was present or not. In both cases norepinephrine-induced contraction was restored in the presence of NG-methyl-L-arginine (300 microM), an inhibitor of nitric oxide synthesis. In interleukin-1-treated rings precontracted with norepinephrine (1 microM), the relaxing response to acetylcholine was totally suppressed independently on the presence of endothelium. High concentrations of acetylcholine (greater than 1 microM) induced a slight contraction which was of lower amplitude than that obtained in control endothelium-denuded rings and was increased in the presence of NG-methyl-L-arginine. These results show that interleukin-1 (i) affects not only vascular contraction but also relaxation and (ii) involves both endothelial and non-endothelial factors. These observations suggest an impairment of the whole vascular reactivity during septic shock.

Acetylcholine↗

PubMed1991

Characterization of beta-adrenoceptor subtypes and indications for two cell populations in isolated bovine mesenteric lymphatic vessels.

The pharmacological characterization of beta-adrenoceptor subtypes and the identification of two cell populations were investigated in isolated bovine mesenteric lymphatic vessels. The beta-adrenoceptor agonists isoprenaline, dobutamine and salbutamol concentration dependently decreased the amplitude and the frequency of spontaneous contractions and the amplitude of electrically induced contractions. The order of potency was isoprenaline greater than salbutamol greater than dobutamine. These effects were competitively antagonized by atenolol with pA2 values close to 7 with isoprenaline and dobutamine as agonists, and near 5.5 with salbutamol as the agonist. Noradrenaline concentration dependently reduced electrically induced contractions, an effect which was reversed to a slight enhancement after blockade of beta-adrenoceptors with propranolol (10(-6) M). These results confirmed the presence of postjunctional beta 1- and beta 2-adrenoceptor subtypes in lymphatic vessels and provide the first indication of the existence of two pharmacologically and functionally distinct cell populations, one of which exhibits pacemaker activity.

Adrenergic beta-Agonists↗

PubMed1989

The role of alpha- and beta-adrenoceptors in the response to noradrenaline of lymphatic vessels isolated from the bovine mesentery.

The role of postsynaptic adrenoceptors in the spontaneous activity of isolated bovine mesenteric lymphatic vessels was characterized. Low concentrations of noradrenaline (less than 10(-6) M) increased the amplitude and the frequency of the spontaneous contractions whereas high concentrations (less than 10(-6) M) depressed the activity. beta-Adrenoceptor blockade with propranolol enhanced the stimulation by noradrenaline and suppressed the inhibition. alpha 1-Blockade by prazosin or alpha 2-blockade by idazoxan antagonized the stimulation by noradrenaline and potentiated the inhibition. Activation of alpha 1-adrenoceptors by methoxamine, or of alpha 2-adrenoceptors by clonidine, stimulated lymphatic activity. The increases in the amplitude and frequency of the spontaneous contractions produced by each agonist were competitively antagonized by prazosin and idazoxan, respectively. Our results confirm the presence of postjunctional beta-, alpha 1-and alpha 2-adrenoceptors in lymphatic vessels and show that each of these receptors plays an important role in the adrenergic regulation of the spontaneous activity, with beta-adrenoceptors mediating inhibition, and alpha 1- and alpha 2-adrenoceptors mediating stimulation.

Animals↗

PubMedDate not supplied

Effects of Daflon 500 mg on bovine vessels contractility.

The effect of Daflon 500 mg, consisting of 90% diosmin and 10% hesperidin, on bovine veins and lymphatic vessels was shown. The recording of mechanical tension on metacarpal vein rings demonstrated a dose-effect relationship with an ED50 of 0.5 X 10(-6) M. This effect observed on isolated organs, is close to the tonic effect of Daflon 500 mg observed in human. An effect was also observed as demonstrated by the depolarisation curve obtained after administration of solutions containing increasing concentrations of potassium. The curve was shifted to the right which may indicate a decrease in potassium permeability in the presence of Daflon 500 mg. On lymphatic vessels isolated from mesenterium, the main effect was an increase in the frequency of spontaneous response which could explain the effect of Daflon 500 mg on lymph flow as shown previously. This dose-effect relationship could be due to an increase in the sensitivity of receptors to some agonists. However, this effect could be pleiotropic. This pleiotropic effect could involve the stimulation by Daflon 500 mg of other cellular mechanisms such as phosphatidylinositol metabolism, or more directly, the pacemaker activity of the cells which govern spontaneous activity, pacemaker activity being under the control of membrane potassium permeability. Some evidence about the action of Daflon 500 mg on potassium permeability could also be shown on other tissues.

Animals↗