Omega-side Chain Research Articles

Structure-activity relationships in a series of 11-deoxy prostaglandins

A series of 11-deoxy prostaglandin derivatives and some naturally occurring prostaglandins have been investigated in the anaesthetized artificially respired guinea-pig for their effect on blood pressure, bronchial resistance (overflow pressure at constant volume), tracheal segment pressure, and on intestinal and uterine smooth muscle. The compounds were administered intravenously. Prostaglandins E 1, E 2 and F 2α produced responses that were qualitatively similar to those in the literature. Prostaglandin A 2 (100 μg) was a bronchoconstrictor, although it decreased tracheal segment pressure and blood pressure. Prostaglandin B 2 (100 μg) caused double elevations in blood pressure, tracheal segment pressure and bronchial resistance. The intensity of bronchoconstriction produced by PGB 2 was of the same order as with PGF 2α. A number of structure-activity relationships were found. 11-Deoxygenation lowered the biological activity of the natural prostaglandins PGE 1 and PGF 1α. The vasodepressor and bronchodilator responses of 11-deoxy PGE 1 were converted to vasopressor and bronchoconstrictor by epimerisation at C-15. Introduction of a methyl group at C-15 of 11-deoxy PGF 1α both increased and prolonged vasopressor and bronchoconstrictor activity. At C-9 both the keto and β-hydroxy group imparted vasodepressor and bronchodilator activity, while the α-hydroxy led to vasopressor and bronchoconstrictor activity. Extension of the omega sidechain by two methylene groups radically reduced the activity of 11-deoxy PGF 1α and its derivatives. These experiments indicate that steric differences in the prostaglandin structures studied can result in diametrically opposed profiles of biological activity. Further, small variations in the prostaglandin molecule can lead to differences in potency and/or profile of activity in the guinea-pig.