Maria Raffaella Romeo

Synthesis of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine, β-adrenergic affinity, inotropic, chronotropic and coronary vasodilating activities

Aseries of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine were synthesized and evaluated for inotropic, chronotropic and coronary vasodilating activities in the canine heart, affinity to beta(1)-adrenergic receptor in turkey erythrocytes and affinity to the beta(2)-adrenergic receptor in the rat lung. Among these compounds, 4-acetyl-6-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 2.1-fold more potent affinity to the beta(1) receptor than propranolol and 7-(3-tert-butylamino-2-hydroxy)propoxy-N-butyryl-3,4-dihydro-2H-1,4-benzoxazine showed 2.5-fold more potent affinity to the beta(2) receptor and furthermore 4386-fold more potent selectivity to the beta(2) receptor than propranolol. In addition, 4-acetyl-6-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 1.1-fold more potent affinity to the beta(1) receptor than propranolol and also 1147-fold more potent selectivity to the beta(1) receptor. With a few exceptions, negative inotropic and chronotropic actions of these compounds were dependent on the size of the 4-substituent obeying the order: unsubstituted < acetyl < propanoyl < butanoyl, while the benzoyl substituent conferred even stronger negative actions in the 6-oxypropanolamine derivatives. Neither negative inotropic and chronotropic actions related with affinity to beta(1)-adrenoceptor nor coronary vasodilator action related with affinity to beta(2)-adrenoceptor were observed. 4-acetyl-7-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxazine exerted potent positive inotropic, chronotropic and coronary vasodilating actions. The inotropic and chronotropic actions of the latter compound may be attributed to the release of intrinsic catecholamines, as concluded by the absence of beta(1)-adrenoceptor affinity and disappearance of activity in the presence of a beta-blocker.

Synthesis and preliminary biological evaluation of 1-aminomethyl-4-substituted-4-H-pyrrolo[2,1-C][1,4] benzothiazines, a new class of calcium antagonists.

Abstract The preparation of 4 a-g , conformationally rigid calcium channel blockers related to Diltiazem, is described starting from tricyclic compounds 5 a-c . On radioreceptor assay and preliminary biochemical tests some compounds show high affinity for Calcium Channel Receptors (CCRs) and calcium antagonistic activity comparable or superior to that of Diltiazem.

MK-801 potentiates the glutathione depletion induced by acetaminophen in rat brain

Abstract To investigate the relationship between acetaminophen (APA) and calcium ion (Ca 2+ ) homeostasis within the glutathione (GSH) oxidation-reduction cycle, male rats were given APA (one buccal injection of 3 g/kg) and/or MK-801 (three intraperitoneal injections each of 0.2 mg/kg), a noncompetitive N-methyl-D-aspartate receptor antagonist. There were injection-vehicle control groups for all active drug groups; an additional control group received no injections (total of seven experimental groups; 134 rats). The brain tissue was examined 8 hours after administration of the drugs to determine the levels of GSH, APA, and protein. APA produced a 25% decrease in GSH that was strongly enhanced by the coadministration of MK-801 (49% decrease). MK-801 alone produced a 32% decrease in brain levels of GSH. This reduction of GSH is probably linked to the interference of Ca 2+ homeostasis and can be considered as a trigger for cell injury in oxidative stress.

Synthesis and in vitro cardiovascular activity of 4-aryl-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazin-1-ones and 7-acetoxy-6-phenyl-7a,8,9,10-tetrahydropyrrolo [2,1-d][1,5]benzothiazepin-10-one

Abstract The synthesis and the pharmacological characterization of novel heterocyclic systems 1 and 2 is described. On radioreceptor assay 1a showed higher affinity for Calcium Channel Receptors (CCRs) and in functional studies higher potency and efficacy as negative inotropic agent than Diltiazem, without relevant calcium antagonist activity on vascular smooth muscle, revealing a clear-cut selectivity for cardiac over vascular tissue.