The Experts below are selected from a list of 102 Experts worldwide ranked by ideXlab platform
Hendrik Timmerman - One of the best experts on this subject based on the ideXlab platform.
-
In vitro and in vivo characterization of a calcium modulator of the Diphenylalkylamine type with selective coronary dilatory properties
Arzneimittel-Forschung, 1997Co-Authors: P Caldirola, A. Monteil, P. Zandberg, Raimund Mannhold, Hendrik TimmermanAbstract:VUF 8929 (N-{2-[bis(p-fluorophenyl)methoxy]ethyl}-(2-phenyl)ethylamine maleate, CAS 140890-71-7) is a Diphenylalkylamine derivative structurally related to prenylamine. The calcium antagonistic properties of this compound have been studied in in vitro and in vivo systems. VUF 8929 has affinity for the voltage-operated calcium channel. Its pK D for the displacement of [ 3 H]nitrendipine bound to cerebral rat cortex is 6.27 (± 0.17). The compound influences the [ 3 H]nitrendipine binding through an allosteric interaction with a site adjacent to the dihydropyridine binding site. Competitive experiments with the additional presence of the phenylalkylamine gallopamil showed that this allosteric site is a property common to diphenyl- and phenylalkylamines. It was further observed that VUF 8929 has a high affinity for calmodulin as it shows high potency in inhibiting the calmodulin mediated activation of PDE. The inhibition of K + (IC 50 0.5 μmol/l)- and noradrenaline (IC 50 1.3 μmol/l)-induced contractions of rabbit aorta rings was in the same concentration range as found for the calmodulin inhibitory activity. In vitro platelet aggregation was also inhibited in the same concentration range when washed platelets were used. Thus calmodulin antagonism may contribute to the observed effects on aorta ring contractions and platelet aggregation. Platelet aggregation, however, in media in which albumin was added or in platelet rich plasma was not affected. It is assumed that due to the high lipophilicity, common to many Diphenylalkylamines, VUF 8929 has a strong binding to plasma proteins. This may also explain why orally administered VUF 8929 did not affect the α 2 -induced pressor response in pithed rats and the ex vivo collagen induced aggregation response. The haemodynamic profile in anaesthetized dogs showed that intravenous injected VUF 8929 reduced the workload of the heart while coronary blood flow increases at a dose of 0.3 mg/kg. Reversible occlusion of the coronary artery, which leads to S-T segment elevation and local venous acidosis, were reduced by VUF 8929 indicating that the compound has anti-ischaemic properties. In conclusion: UVF 8929 is a calcium antagonist which has anti-ischaemic properties, reduces the workload of the heart and increases coronary flow. Due to these properties VUF 8929 is a potential cardioprotective agent.
-
Prenylamine derivatives as blockers of the vesicular transporter for dopamine. A quantitative structure-activity study
European Journal of Medicinal Chemistry, 1997Co-Authors: A Vaccari, Pl Saba, Mp Caldirola, Greetje J. Bijloo, Hendrik TimmermanAbstract:Summary A new series of Diphenylalkylamine congeners of prenylamine have been assayed in binding experiments on rat striatal membrane preparations. The aim was to ascertain the influence of structural modifications and lipophilicity on their interaction with the [ 3 H]tyramine-labeled vesicular transporter for dopamine. Thirteen compounds potently inhibited the specific binding of [ 3 H]tyramine, with nanomolar K i , values in the range of those of established markers for the vesicular transporter of dopamine. Less lipophilic compounds displayed higher affinity for the energy-dependent amine transporter.
-
New prenylamine-analogues: investigations of their influence on calcium-dependent biological systems
European Journal of Medicinal Chemistry, 1993Co-Authors: P Caldirola, P. Zandberg, Raimund Mannhold, Hendrik TimmermanAbstract:Abstract Chemically, prenylamine belongs to the Diphenylalkylamine class. Compounds of this class are calcium antagonists with a broad spectrum of activities due to their influence on both extracellular and intracellular sites. In the present study the calcium antagonistic profile of a recently developed new series of prenylamine analogues has been investigated using different in vitro systems. The inhibiting concentrations for the most active compound are ≈ 1.5 μM; several derivatives are inactive up to a concentration of 10 μM. Structural modifications towards an increase of lipophilicity make these molecules interact (inhibition) with the intracellular calcium-binding protein calmodulin; for the series no correlation between calcium-blocking and calmodulin antagonistic effects has been found.
-
New calmodulin-antagonists of the Diphenylalkylamine type. II. QSAR investigations by means of partial least square (PLS) analysis
European Journal of Medicinal Chemistry, 1993Co-Authors: P Caldirola, Raimund Mannhold, H. Van Der Goot, E Coats, Hendrik TimmermanAbstract:Abstract Quantitative structure-activity relationships for a series of 71 Diphenylalkylamines which possesses a relatively high capacity of interfering with calmodulin have been reported. Partial least square (PLS) analysis was used to obtain detailed information on structural features affecting calmodulin antagonistic activity. Apart from lipophilicity, structural parameters also strongly influence the activity. Chain length, the presence and/or absence of the methyl group vicinal to the nitrogen atom, the methylation of the nitrogen atom as well as the presence of the oxygen as heteroatom in combination with benzhydryl substitution have been indicated as the most important molecular descriptors. The model thus provided by PLS analysis successfully predicted the biological activities of additional newly synthesized prenylamine derivatives.
-
New calmodulin antagonists of the Diphenylalkylamine type. I. Biological activity, SAR and the role of lipophilicity
European Journal of Medicinal Chemistry, 1993Co-Authors: Raimund Mannhold, P Caldirola, Greetje J. Bijloo, Hendrik TimmermanAbstract:Abstract Potency and selectivity of currently available calmodulin (CaM) antagonists is rather limited. We attempted to improve the CaM-antagonistic activity in a new series of analogues of the CaM-antagonist prenylamine. The biological test system used was the CaM-stimulated phosphodiesterase. Insertion of a double bond or heteroatoms (O, S) at the ring connecting carbon in the benzhydryl part of the molecule increases potency in comparison to the lead compound prenylamine. Chain length is optimal with 4 atoms-nitrogen-3 atoms. Regarding benzhydryl substitution, halogenation results in a significantly increased improvement of CaM-inhibitory potency than methylation; para -substitution is superior to ortho -substitution. Secondary nitrogen seems to be advantageous as compared to tertiary amine. Lipophilicity has been detected as a prime physico-chemical descriptor of CaM-antagonistic potency. The role of lipophilicity, however, differs in a quantitative sense when the subgroups are considered. It decreases within the subgroups in the following manner: saturated alkyl chain- > double bond > sulphur- > oxygen-derivatives. Amongst the compounds described, new CaM-antagonists with remarkably high potency have been detected.
Helmut A. Tritthart - One of the best experts on this subject based on the ideXlab platform.
-
Fendiline inhibits L-type calcium channels in guinea-pig ventricular myocytes: a whole-cell patch-clamp study
British journal of pharmacology, 1993Co-Authors: Onkar Tripathi, Wolfgang Schreibmayer, Helmut A. TritthartAbstract:1. Fendiline, a Diphenylalkylamine type of antianginal drug, was examined for its effects on L-type calcium channels in guinea-pig ventricular myocytes by the whole-cell patch-clamp technique. 2. Fendiline (0.3-100 microM) applied extracellularly inhibited the calcium channel current (ICa) in a concentration- and time-dependent manner. The IC50 of fendiline was 17.0 +/- 2.43 microM and the Hill slope was 1.39 +/- 0.23. 3. Inhibition of ICa by fendiline appeared with an onset of less than 3 s. 4. Fendiline inhibited ICa at all the membrane potentials tested and shifted the current-voltage curve upwards. The overall calcium channel conductance (gCa) of the cell was reduced and conductance-voltage curve was shifted to the left in the presence of fendiline. 5. Isoprenaline (0.5-1 microM), a beta-adrenoceptor agonist, partially reversed the inhibitory effect of fendiline on ICa. 6. It is suggested that fendiline applied extracellularly blocks L-type calcium channels and reduces calcium channel conductance of the cell. The calcium channels thus inhibited are, nevertheless, still available for beta-adrenoceptor stimulation.
-
Kinetic modulation of guinea-pig cardiac L-type calcium channels by fendiline and reversal of the effects of Bay K 8644.
British journal of pharmacology, 1992Co-Authors: Wolfgang Schreibmayer, Onkar Tripathi, Helmut A. TritthartAbstract:Abstract 1. The modulation of L-type calcium channel current (ICa) by fendiline, a Diphenylalkylamine type of calcium channel blocker was investigated on guinea-pig ventricular myocytes by use of the whole-cell patch-clamp technique. 2. Fendiline-induced block of ICa is accompanied by modulation of the channel kinetics in a complex manner. The time course of ICa inactivation is significantly faster and the channel availability (f infinity) curve is shifted considerably to more negative potentials by fendiline. These findings can be interpreted qualitatively in terms of a modulated receptor. 3. When the 1,4-dihydropyridine agonist (4R, 4S)-Bay K 8644 was added in presence of 30 microM fendiline a further reduction of ICa instead of the expected stimulatory effect was observed. 4. A similar 'paradoxical' inhibition of ICa was produced by the pure agonist enantiomer (4S)-Bay K 8644. Thus this novel effect of Bay K 8644 cannot be attributed to changes in affinity of the 1,4-dihydropyridine receptor site for (4R)-Bay K 8644 during fendiline action. 5. The IC50 for fendiline was reduced to 3.0 +/- 0.1 microM (control value: 17.0 +/- 2.4 microM) and the Hill slope in its presence was increased to 1.90 +/- 0.1 (control value: 1.39 +/- 0.23) by 1 microM (4R, 4S)-Bay K 8644. 6. (4R,4S)-Bay K 8644 caused the expected stimulation of ICa in the presence of verapamil, diltiazem and nifedipine, overcoming the inhibitory effect of these calcium channel blockers. 7. The 'paradoxical' inhibitory effect of the agonist Bay K 8644 can be explained in terms of an allosteric interaction between fendiline and the dihydropyridine agonist.
P Caldirola - One of the best experts on this subject based on the ideXlab platform.
-
In vitro and in vivo characterization of a calcium modulator of the Diphenylalkylamine type with selective coronary dilatory properties
Arzneimittel-Forschung, 1997Co-Authors: P Caldirola, A. Monteil, P. Zandberg, Raimund Mannhold, Hendrik TimmermanAbstract:VUF 8929 (N-{2-[bis(p-fluorophenyl)methoxy]ethyl}-(2-phenyl)ethylamine maleate, CAS 140890-71-7) is a Diphenylalkylamine derivative structurally related to prenylamine. The calcium antagonistic properties of this compound have been studied in in vitro and in vivo systems. VUF 8929 has affinity for the voltage-operated calcium channel. Its pK D for the displacement of [ 3 H]nitrendipine bound to cerebral rat cortex is 6.27 (± 0.17). The compound influences the [ 3 H]nitrendipine binding through an allosteric interaction with a site adjacent to the dihydropyridine binding site. Competitive experiments with the additional presence of the phenylalkylamine gallopamil showed that this allosteric site is a property common to diphenyl- and phenylalkylamines. It was further observed that VUF 8929 has a high affinity for calmodulin as it shows high potency in inhibiting the calmodulin mediated activation of PDE. The inhibition of K + (IC 50 0.5 μmol/l)- and noradrenaline (IC 50 1.3 μmol/l)-induced contractions of rabbit aorta rings was in the same concentration range as found for the calmodulin inhibitory activity. In vitro platelet aggregation was also inhibited in the same concentration range when washed platelets were used. Thus calmodulin antagonism may contribute to the observed effects on aorta ring contractions and platelet aggregation. Platelet aggregation, however, in media in which albumin was added or in platelet rich plasma was not affected. It is assumed that due to the high lipophilicity, common to many Diphenylalkylamines, VUF 8929 has a strong binding to plasma proteins. This may also explain why orally administered VUF 8929 did not affect the α 2 -induced pressor response in pithed rats and the ex vivo collagen induced aggregation response. The haemodynamic profile in anaesthetized dogs showed that intravenous injected VUF 8929 reduced the workload of the heart while coronary blood flow increases at a dose of 0.3 mg/kg. Reversible occlusion of the coronary artery, which leads to S-T segment elevation and local venous acidosis, were reduced by VUF 8929 indicating that the compound has anti-ischaemic properties. In conclusion: UVF 8929 is a calcium antagonist which has anti-ischaemic properties, reduces the workload of the heart and increases coronary flow. Due to these properties VUF 8929 is a potential cardioprotective agent.
-
New prenylamine-analogues: investigations of their influence on calcium-dependent biological systems
European Journal of Medicinal Chemistry, 1993Co-Authors: P Caldirola, P. Zandberg, Raimund Mannhold, Hendrik TimmermanAbstract:Abstract Chemically, prenylamine belongs to the Diphenylalkylamine class. Compounds of this class are calcium antagonists with a broad spectrum of activities due to their influence on both extracellular and intracellular sites. In the present study the calcium antagonistic profile of a recently developed new series of prenylamine analogues has been investigated using different in vitro systems. The inhibiting concentrations for the most active compound are ≈ 1.5 μM; several derivatives are inactive up to a concentration of 10 μM. Structural modifications towards an increase of lipophilicity make these molecules interact (inhibition) with the intracellular calcium-binding protein calmodulin; for the series no correlation between calcium-blocking and calmodulin antagonistic effects has been found.
-
New calmodulin-antagonists of the Diphenylalkylamine type. II. QSAR investigations by means of partial least square (PLS) analysis
European Journal of Medicinal Chemistry, 1993Co-Authors: P Caldirola, Raimund Mannhold, H. Van Der Goot, E Coats, Hendrik TimmermanAbstract:Abstract Quantitative structure-activity relationships for a series of 71 Diphenylalkylamines which possesses a relatively high capacity of interfering with calmodulin have been reported. Partial least square (PLS) analysis was used to obtain detailed information on structural features affecting calmodulin antagonistic activity. Apart from lipophilicity, structural parameters also strongly influence the activity. Chain length, the presence and/or absence of the methyl group vicinal to the nitrogen atom, the methylation of the nitrogen atom as well as the presence of the oxygen as heteroatom in combination with benzhydryl substitution have been indicated as the most important molecular descriptors. The model thus provided by PLS analysis successfully predicted the biological activities of additional newly synthesized prenylamine derivatives.
-
New calmodulin antagonists of the Diphenylalkylamine type. I. Biological activity, SAR and the role of lipophilicity
European Journal of Medicinal Chemistry, 1993Co-Authors: Raimund Mannhold, P Caldirola, Greetje J. Bijloo, Hendrik TimmermanAbstract:Abstract Potency and selectivity of currently available calmodulin (CaM) antagonists is rather limited. We attempted to improve the CaM-antagonistic activity in a new series of analogues of the CaM-antagonist prenylamine. The biological test system used was the CaM-stimulated phosphodiesterase. Insertion of a double bond or heteroatoms (O, S) at the ring connecting carbon in the benzhydryl part of the molecule increases potency in comparison to the lead compound prenylamine. Chain length is optimal with 4 atoms-nitrogen-3 atoms. Regarding benzhydryl substitution, halogenation results in a significantly increased improvement of CaM-inhibitory potency than methylation; para -substitution is superior to ortho -substitution. Secondary nitrogen seems to be advantageous as compared to tertiary amine. Lipophilicity has been detected as a prime physico-chemical descriptor of CaM-antagonistic potency. The role of lipophilicity, however, differs in a quantitative sense when the subgroups are considered. It decreases within the subgroups in the following manner: saturated alkyl chain- > double bond > sulphur- > oxygen-derivatives. Amongst the compounds described, new CaM-antagonists with remarkably high potency have been detected.
-
Novel stereoselective calcium channel ligands of the Diphenylalkylamine-type
Bioorganic & Medicinal Chemistry Letters, 1992Co-Authors: M. Q. Zhang, P Caldirola, Dirk Leysen, Hendrik TimmermanAbstract:Abstract The optically pure enantiomers of α-(4-chlorophenyl)-α-phenyl-1-(4-tert-butylphenyl)butyl]-4-piperidinemethanol were synthesized and tested for calcium channel affinity on rat brain membranes. The levo-isomer (VUF4648) was found to exert a 190 times stronger inhibition of [3H]nitrendipine binding than the dextro-isomer (VUF4647). Implications for the action mechanism of this type of compounds are discussed.
Onkar Tripathi - One of the best experts on this subject based on the ideXlab platform.
-
Fendiline inhibits L-type calcium channels in guinea-pig ventricular myocytes: a whole-cell patch-clamp study
British journal of pharmacology, 1993Co-Authors: Onkar Tripathi, Wolfgang Schreibmayer, Helmut A. TritthartAbstract:1. Fendiline, a Diphenylalkylamine type of antianginal drug, was examined for its effects on L-type calcium channels in guinea-pig ventricular myocytes by the whole-cell patch-clamp technique. 2. Fendiline (0.3-100 microM) applied extracellularly inhibited the calcium channel current (ICa) in a concentration- and time-dependent manner. The IC50 of fendiline was 17.0 +/- 2.43 microM and the Hill slope was 1.39 +/- 0.23. 3. Inhibition of ICa by fendiline appeared with an onset of less than 3 s. 4. Fendiline inhibited ICa at all the membrane potentials tested and shifted the current-voltage curve upwards. The overall calcium channel conductance (gCa) of the cell was reduced and conductance-voltage curve was shifted to the left in the presence of fendiline. 5. Isoprenaline (0.5-1 microM), a beta-adrenoceptor agonist, partially reversed the inhibitory effect of fendiline on ICa. 6. It is suggested that fendiline applied extracellularly blocks L-type calcium channels and reduces calcium channel conductance of the cell. The calcium channels thus inhibited are, nevertheless, still available for beta-adrenoceptor stimulation.
-
Kinetic modulation of guinea-pig cardiac L-type calcium channels by fendiline and reversal of the effects of Bay K 8644.
British journal of pharmacology, 1992Co-Authors: Wolfgang Schreibmayer, Onkar Tripathi, Helmut A. TritthartAbstract:Abstract 1. The modulation of L-type calcium channel current (ICa) by fendiline, a Diphenylalkylamine type of calcium channel blocker was investigated on guinea-pig ventricular myocytes by use of the whole-cell patch-clamp technique. 2. Fendiline-induced block of ICa is accompanied by modulation of the channel kinetics in a complex manner. The time course of ICa inactivation is significantly faster and the channel availability (f infinity) curve is shifted considerably to more negative potentials by fendiline. These findings can be interpreted qualitatively in terms of a modulated receptor. 3. When the 1,4-dihydropyridine agonist (4R, 4S)-Bay K 8644 was added in presence of 30 microM fendiline a further reduction of ICa instead of the expected stimulatory effect was observed. 4. A similar 'paradoxical' inhibition of ICa was produced by the pure agonist enantiomer (4S)-Bay K 8644. Thus this novel effect of Bay K 8644 cannot be attributed to changes in affinity of the 1,4-dihydropyridine receptor site for (4R)-Bay K 8644 during fendiline action. 5. The IC50 for fendiline was reduced to 3.0 +/- 0.1 microM (control value: 17.0 +/- 2.4 microM) and the Hill slope in its presence was increased to 1.90 +/- 0.1 (control value: 1.39 +/- 0.23) by 1 microM (4R, 4S)-Bay K 8644. 6. (4R,4S)-Bay K 8644 caused the expected stimulation of ICa in the presence of verapamil, diltiazem and nifedipine, overcoming the inhibitory effect of these calcium channel blockers. 7. The 'paradoxical' inhibitory effect of the agonist Bay K 8644 can be explained in terms of an allosteric interaction between fendiline and the dihydropyridine agonist.
Andrea Vaccari - One of the best experts on this subject based on the ideXlab platform.
-
Potent, extra-channel influence of several calcium-channel modulators on striatal binding of [^3H]tyramine
Neurochemical Research, 1993Co-Authors: Andrea Vaccari, Pierluigi Saba, Gianluigi GessaAbstract:A number of Ca^2+-, K^+-, and Na^+-channel modulators has been tested with respect to their effects on [^3H]tyramine (TY) binding, as a putative marker for the vesicular dopamine (DA) transporter in striatal membrane preparations containing vesicle ghosts. Among organic Ca^2+-channel modulators, the Diphenylalkylamines tested consistently inhibited TY binding: the order of potency was prenylamine>lidoflazine>flunarizine>cinnarizine, with K_i values of 0.1, 0.2, 0.5 and 1.2 μM, respectively. Low (up to 100 nM) concentrations of prenylamine did competitively inhibit TY binding, and higher concentrations provoked a mixed-type inhibition. Furthermore, LIGAND-analysis of competition curves revealed a high- and a low-affinity binding site for prenylamine and flunarizine. The TY binding process was also sensitive to selected K^+- and Na^+-channel modulators. Since several Ca^2+-antagonists are known to affect H^+-ATPase and the bioenergetics of catecholamine storage vesicles in chromaffin granules, thus affecting monoamine storage, the energy requirements for the formation of the TY/carrier complex were here assessed, assuming similarity between chromaffin granules and synaptic vesicles. TY binding, though not reflecting endovesicle-sequestered TY, was indeed strongly sensitive (with K_i coefficients in the fM or low nM range) to the dissipation of the vesicular transmembrane proton concentration (Δ pH), electrical (Δ Ψ), and proton electrochemical (Δ μH^+) gradients, provoked by a number of specifically targeted agents. It is concluded that Ca^2+-channel agents of the Diphenylalkylamine group may directly affect striatal TY binding due to an extrachannel-regulated competition with TY for the vesicular carrier of DA, as well indirectly, by disruption of the transmembrane energization of the reserpine-sensitive carrier.
-
The tyramine binding site in the central nervous system: An overview
Neurochemical Research, 1993Co-Authors: Andrea VaccariAbstract:The [^3H]Tyramine (TY) binding site is proposed as a high affinity marker of the membrane carrier for dopamine (DA) in synaptic vesicles from DA-rich brain regions. Under precise assay conditions, there is neither a consistent association of TY with the neuronal, cocaine-sensitive DA transporter, nor with mitochondrial or microsomal targets. TY-labeled sites have a high affinity for selected toxins such as the Parkinsonian agent MPP^+ (1-methyl-4-phenylpyridinium ion), or drugs such as Diphenylalkylamine Ca^2+-channel antagonists. The MPP^+/TY site interaction, which in the striatum leads to depletion of vesicular DA, occurs in dopaminergic as well as in noradrenergic regions, though with different kinetic profiles. TY-labeled carriers for DA and noradrenaline (NA) in respective vesicles seem to be different entities, which might result in a region-specific rate of toxin sequestration and/or release from heterogeneous vesicles. Whereas MPP^+ is a potent competitive-type inhibitor of [^3H]TY binding, prenylamine-like Ca^2+-channel antagonists can compete with TY for the vesicle site, in a tetrabenazine- or reserpine-like manner, and also inhibit TY binding thanks to the extra-channel directed impairment of membrane bioenergetics they are proposed to provoke. This follows from the generally-accepted assumption that similar mechanisms are operational for secretory organelles in adrenals and CNS, and from the marked sensitivity of TY binding to miscellaneous energy-disrupting agents. A model is therefore proposed, depicting the TY-, DA- or MPP^+-labeled, vesicle carrier, as a dimeric protein which may switch from the cytoplasm-oriented, “recognition” state, to the vesicle-oriented, “transport” state, thanks to the establishment of an H^+-ATPase-supported, membrane protein electrochemical gradient.