Comparative effects of some 3-amino 4,6-diarylpyridazines on the biosynthesis in vitro of TXA2 and PGI2- and on the TXA2- and PGI2-synthesizing activities of cardiac tissue.
Some 3-amino 4,6-diarylpyridazine derivatives were tested for their effects on TXA2 and PGI2 biosyntheses in vitro and on the TXA2- and PGI2-synthesizing activities of cardiac tissue. Horse platelet and aorta microsomes were used as sources of thromboxane and prostacyclin synthetases respectively. The TXA2- and PGI2-synthesizing activities of cardiac tissue were studied on isolated perfused rabbit hearts (the heart microsomes being used both as TXA2 synthetase and PGI2 synthetase sources). TXB2 and 6-keto PGF1 alpha were determined by RIA. Among the compounds under study, 3-morpholino 4,6-diphenylpyridazine (III) was shown to inhibit specifically the TXA2 synthetase. Substitution of the morpholino group by a dimethylamino one (I) reinforced the inhibiting effects on TXA2 synthetase but it also revealed a slight anti-prostacyclin synthetase action of the molecule. Replacement of 3-morpholino moieties by either a 3-hydrazino (IV), or a 2-dimethylaminoethylamino (V), or a 2-morpholinoethylamino group (VI) abolished completely the effects of the molecule on TXA2 and PGI2 synthetases. Likewise the addition of chlorine on the para-position on the phenyl ring of I neutralized all its inhibitory effects both on TXA2 and PGI2 synthetases in vitro. None of the 3-amino 4,6-diarylpyridazine derivatives was active on either the TXA2- or PGI2-synthesizing activities of cardiac tissue.
Pham
H C
HC
Pharmacologie de la Régulation, CNRS Institute de Physiologie, Toulouse, France.
Dossou-Gbete
V
V
Kaiser
R
R
Lasserre
B
B
Chahine
R
R
Couquelet
J
J
Coudert
P
P
Rubat
C
C
D000818:Animals; D011464:Epoprostenol / Q000096:biosynthesis*; D006736:Horses; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology*; D011817:Rabbits; D013928:Thromboxane A2 / Q000096:biosynthesis*
D011724:Pyridazines; D013928:Thromboxane A2; D011464:Epoprostenol