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Binding kinetics and antiplatelet activities of picotamide, a thromboxane A 2 receptor antagonist
Author(s) -
Modesti Pietro Amedeo,
Cecioni Ilaria,
Colella Andrea,
Costoli Alessandro,
Paniccia Rita,
Serneri Gian Gastone Neri
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb13033.x
Subject(s) - platelet , chemistry , thromboxane a2 , thromboxane , prostacyclin , thromboxane a synthase , prostaglandin h2 , receptor , receptor–ligand kinetics , antagonist , platelet activation , binding site , kinetics , receptor antagonist , medicine , pharmacology , endocrinology , biochemistry , physics , quantum mechanics
1 Picotamide was shown to inhibit platelet binding of thromboxane A 2 (TxA 2 )‐mimetics and to cause a reduction of TxA 2 platelet receptors after in vivo administration. The present study aimed to investigate directly [ 3 H]‐picotamide binding to human platelets and in particular the relationship between binding kinetics and antiaggregating properties. 2 [ 3 H]‐picotamide time‐dependently bound to a single class of platelet TxA 2 receptors with a K D of 325 nmol l −1 at equilibrium. The binding was displaceable by TxA 2 analogues U46619 and ONO11120 ( K i 19 and 28 nmol l −1 respectively) but not by prostacyclin (PGI 2 ), prostaglandin E 2 (PGE 2 ) and TxB 2 . Antiaggregating activity and TxA 2 formation inhibition paralleled with binding kinetics. 3 By prolonging the incubation time from 30 to 120 min, picotamide showed a progressively increasing non‐displaceable binding, whereas specific displaceable binding decreased in comparison to the values reached at 30 min. Non displaceable binding was specific, temperature‐dependent, saturable and followed a Michaelis‐Menten kinetic (V maxapp = 130 fmol per 10 8 platelets h −1 , K Mapp = 330 nmol l −1 ). Picotamide progressively underwent a specific stable interaction with its platelet receptor. 4 In conclusion, after an initial reversible binding, a progressive stabilization of picotamide binding takes place resulting in a progressively more stable interaction with platelets.