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Iakovou K, Kazanis M, Vavayannis A, et al. Synthesis of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine, beta-adrenergic affinity, inotropic, chronotropic and coronary vasodilating activities. Eur J Med Chem. 1999;34(11):903-917doi: 10.1016/s0223-5234(99)00109-9.
Iakovou, K., Kazanis, M., Vavayannis, A., Bruni, G., Romeo, M. R., Massarelli, P., Teramoto, S., Fujiki, H., & Mori, T. (1999). Synthesis of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine, beta-adrenergic affinity, inotropic, chronotropic and coronary vasodilating activities. European journal of medicinal chemistry, 34(11), 903-917. https://doi.org/10.1016/s0223-5234(99)00109-9
Iakovou, et al. "Synthesis of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine, beta-adrenergic affinity, inotropic, chronotropic and coronary vasodilating activities." European journal of medicinal chemistry vol. 34,11 (1999): 903-917. doi: https://doi.org/10.1016/s0223-5234(99)00109-9
Iakovou K, Kazanis M, Vavayannis A, Bruni G, Romeo MR, Massarelli P, Teramoto S, Fujiki H, Mori T. Synthesis of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine, beta-adrenergic affinity, inotropic, chronotropic and coronary vasodilating activities. Eur J Med Chem. 1999 Nov 01;34(11):903-917. doi: 10.1016/s0223-5234(99)00109-9. PMID: 10889316.
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Eur J Med Chem. 1999 Nov 01;34(11):903-917. doi: 10.1016/s0223-5234(99)00109-9.

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

European journal of medicinal chemistry

Iakovou, Kazanis, Vavayannis, Bruni, Romeo, Massarelli, Teramoto, Fujiki, Mori

Affiliations

  1. Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens, Panepistimiopolis Zografou, GR-157 71, Athens, Greece

PMID: 10889316 DOI: 10.1016/s0223-5234(99)00109-9

Abstract

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.

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