Binding and competitive inhibition of amine uptake at postsynaptic neurones (transport-P) by tricyclic antidepressants

The effects of viloxazine, a clinically effective antidepressant, on noradrenaline (NA) and 5-hydroxytryptamine (5-HT) uptake and various related pharmacological activities were determined and compared to those of the tricyclic antidepressants desimipramine, imipramine, and amitriptyline.Viloxazine inhibited [3H]NA uptake in the mouse and rat heart, being maximally about one half as potent as imipramine with a similar onset, but shorter duration of action than imipramine. The drug did not inhibit [3H]NA uptake in rat medulla or hypothalamus in contrast to desimipramine and imipramine, but it did alter [3H]NA metabolites in a similar manner. Viloxazine, like desimipramine, was a weak blocker of mouse brain 5-HT uptake, but differed from desimipramine as it potentiated 5-HT-mediated functions in the mouse and rat, as did imipramine and amitriptyline, the latter drugs being relatively potent blockers of 5-HT uptake.Viloxazine potentiated the L-DOPA behavioural syndrome in the mouse, antagonized reserpine-induced ptosis and hypothermia in the mouse, and inhibited gastric acid secretion in the rat, but was less potent than the tricyclic antidepressants. No appreciable in vivo inhibition of monoamine oxidase (EC 1.4.3.4.) activity in the mouse was exhibited. Like imipramine, the drug potentiated the ocular effects of L-adrenaline in the rabbit. It was similar to imipramine in potency in potentiating the apomorphine-induced gnawing in the mouse. The drug antagonized oxotremorine-induced hypothermia in the mouse but differed from, the tricyclic antidepressants in not exhibiting the anticholinergic effects of blocking the tremors, salivation and lacrimation.Thus, viloxazine exhibits activities related to the biogenic amines both similar to and different from the tricyclics desimipramine, imipramine, and amitriptyline. These actions appear to be of relevance with respect to the antidepressant action of this drug.

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Effects of various tricyclic antidepressants on amine uptake

European Journal of Pharmacology ◽

10.1016/0014-2999(86)90640-0 ◽

1986 ◽

Vol 120 (1) ◽

pp. 63-68 ◽

Cited By ~ 5

Author(s):

Koichi Ishikawa ◽

Shinji Shibanoki ◽

Taizo Kubo ◽

Shigeo Watabe ◽

Akira Matsumoto ◽

...

Keyword(s):

Tricyclic Antidepressants ◽

Amine Uptake

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Anti-allodynic effecis of tricyclic antidepressants in TNBS-induced chronic colonic hypersensitivity

Gastroenterology ◽

10.1016/s0016-5085(01)81635-8 ◽

2001 ◽

Vol 120 (5) ◽

pp. A329-A329

Author(s):

S CASET ◽

C BERTRAND ◽

A DOHERTY

Keyword(s):

Tricyclic Antidepressants

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Review of Living With Tricyclic Antidepressants.

Contemporary Psychology ◽

10.1037/000064 ◽

1997 ◽

Vol 42 (1) ◽

pp. 84-84

Author(s):

Terri Gullickson

Keyword(s):

Tricyclic Antidepressants

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Tracking the dynamics of global and competitive inhibition in early and late adulthood: Evidence from the flanker task.

Psychology and Aging ◽

10.1037/pag0000435 ◽

2020 ◽

Vol 35 (5) ◽

pp. 729-743 ◽

Cited By ~ 1

Author(s):

Christopher D. Erb ◽

Dayna R. Touron ◽

Stuart Marcovitch

Keyword(s):

Competitive Inhibition ◽

Flanker Task ◽

Late Adulthood

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Ristocetin and Botrocetin Involve Two Distinct Domains of von Willebrand Factor for Binding to Platelet Membrane Glycoprotein lb

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647310 ◽

1990 ◽

Vol 64 (02) ◽

pp. 326-332 ◽

Cited By ~ 57

Author(s):

J P Girma ◽

Y Takahashi ◽

A Yoshioka ◽

J Diaz ◽

D Meyer

Keyword(s):

Von Willebrand Factor ◽

Synthetic Peptides ◽

Competitive Inhibition ◽

Final Concentration ◽

Binding Domain ◽

Platelet Membrane ◽

Platelet Glycoprotein ◽

Membrane Glycoprotein ◽

Von Willebrand ◽

Willebrand Factor

SummaryWe have evidence that ristocetin and botrocetin mediate binding of von Willebrand Factor (vWF) to platelet glycoprotein lb (GPIb) through two distinct domains on the vWF molecule. This was established by using monoclonal antibodies (MAbs) to vWF and synthetic peptides derived from the sequence of vWF. MAb 322 and MAb NMC/vW 4 both recognize native vWF as well as fragments containing the GPIb-binding domain of vWF, obtained with the following enzymes: trypsin (116 kDa), V-8 pro tease (Spill, 320 kDa) and V-8 protease plus subtilisin (33-28 kDa). Nevertheless, the lack of reciprocal displacement between the two MAbs in experiments of competitive inhibition for binding to vWF demonstrate that their respective epitopes are separate. Both MAbs inhibit 125I-vWF binding to platelet membrane GPIb and vWF-dependent platelet agglutination induced by ristocetin. However, only MAb NMC/vW4 inhibits these functions in the presence of botrocetin and when ristocetin-induced platelet agglutination is inhibited by MAb 322, botrocetin is still able to restore the agglutination. The involvement of two distinct domains of vWF for binding to GPIb in the presence of ristocetin or botrocetin was confirmed in experiments of binding of 125I-vWF to platelets using as competitor synthetic peptides corresponding to the GPIb binding domain of vWF (Cys 474 to Pro 488 and Ser 692 to Pro 708). At a final concentration of 2.5 mM both peptides inhibit more than 90% of the binding of vWF to ristocetin-treated platelets but are unable to modify this binding in the presence of botrocetin. In conclusion our data suggest that botrocetin and ristocetin involve distinct sites on vWF for binding to GPIb.

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Kinetic Aspects of the Interaction of Blood Clotting Enzymes

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651214 ◽

1968 ◽

Vol 19 (03/04) ◽

pp. 364-367 ◽

Cited By ~ 4

Author(s):

H. C Hemker ◽

P. W Hemker

Keyword(s):

Enzyme Kinetics ◽

Blood Clotting ◽

Competitive Inhibition ◽

Competitive Inhibitor ◽

Kinetics Of

SummaryThe enzyme kinetics of competitive inhibition under conditions prevailing in clotting tests are developed and a method is given to measure relative amounts of a competitive inhibitor by means of the t — D plot.

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Effects of Dipyrone on Prostaglandin Production by Human Platelets and Cultured Bovine Aortic Endothelial Cells

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657338 ◽

1983 ◽

Vol 49 (02) ◽

pp. 132-137 ◽

Cited By ~ 16

Author(s):

A Eldor ◽

G Polliack ◽

I Vlodavsky ◽

M Levy

Keyword(s):

Endothelial Cells ◽

Arachidonic Acid ◽

Competitive Inhibition ◽

Inhibitory Effect ◽

Human Platelets ◽

Ionophore A23187 ◽

Aortic Endothelial Cells ◽

Bovine Aortic Endothelial Cells ◽

Aortic Endothelial

SummaryDipyrone and its metabolites 4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoan- tipyrine inhibited the formation of thromboxane A2 (TXA2) during in vitro platelet aggregation induced by ADP, epinephrine, collagen, ionophore A23187 and arachidonic acid. Inhibition occurred after a short incubation (30–40 sec) and depended on the concentration of the drug or its metabolites and the aggregating agents. The minimal inhibitory concentration of dipyrone needed to completely block aggregation varied between individual donors, and related directly to the inherent capacity of their platelets to synthesize TXA2.Incubation of dipyrone with cultured bovine aortic endothelial cells resulted in a time and dose dependent inhibition of the release of prostacyclin (PGI2) into the culture medium. However, inhibition was abolished when the drug was removed from the culture, or when the cells were stimulated to produce PGI2 with either arachidonic acid or ionophore A23187.These results indicate that dipyrone exerts its inhibitory effect on prostaglandins synthesis by platelets or endothelial cells through a competitive inhibition of the cyclooxygenase system.

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The Kinetics of Inhibition of the Action of Thrombin by the Fibrinopeptides Formed during the Clotting of Fibrinogen

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655562 ◽

1966 ◽

Vol 16 (01/02) ◽

pp. 277-295 ◽

Cited By ~ 1

Author(s):

A Silver ◽

M Murray

Keyword(s):

Amino Acids ◽

Competitive Inhibition ◽

Amorphous Material ◽

Peptide Bond ◽

Initial Reaction ◽

Reaction Products ◽

Coagulation Mechanism ◽

Kinetics Of ◽

Kinetics Of Inhibition ◽

Burk Plot

SummaryVarious investigators have separated the coagulation products formed when fibrinogen is clotted with thrombin and identified fibrinopeptides A and B. Two other peaks are observed in the chromatogram of the products of coagulation, but these have mostly been dismissed by other workers. They have been identified by us as amino acids, smaller peptides and amorphous material (37). We have re-chromatographed these peaks and identified several amino acids. In a closed system of fibrinogen and thrombin, the only reaction products should be fibrin and peptide A and peptide B. This reasoning has come about because thrombin has been reported to be specific for the glycyl-arginyl peptide bond. It is suggested that thrombin also breaks other peptide linkages and the Peptide A and Peptide B are attacked by thrombin to yield proteolytic products. Thrombin is therefore probably not specific for the glycyl-arginyl bond but will react on other linkages as well.If the aforementioned is correct then the fibrinopeptides A and B would cause an inhibition with the coagulation mechanism itself. We have shown that an inhibition does occur. We suggest that there is an autoinhibition to the clotting mechanism that might be a control mechanism in the human body.The experiment was designed for coagulation to occur under controlled conditions of temperature and time. Purified reactants were used. We assembled an apparatus to record visually the speed of the initial reaction, the rate of the reaction, and the density of the final clot formed after a specific time.The figures we derived made available to us data whereby we could calculate and plot the information to show the mechanism and suggest that such an inhibition does exist and also further suggest that it might be competitive.In order to prove true competitive inhibition it is necessary to fulfill the criteria of the Lineweaver-Burk plot. This has been done. We have also satisfied other criteria of Dixon (29) and Bergman (31) that suggest true competitive inhibition.

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