Interaction of new 19 nor progesterone derivatives with progestagen, mineralocorticoid and glucocorticoid cytosolic receptors.

Abstract

Structure-activity relationships were studied in vitro on a number of natural and artificial steroids in order to assess their progestagen specificity. These substances included a new compound derived from 19 nor progesterone, TX066 or nomegestrol acetate, and two synthetic intermediates, TX045 and TX071, all prepared by Laboratoires Theramex. The experiments involved binding competition on the cytosolic receptors prepared from target organs against specific radiolabelled ligands. Relative affinities were determined in rats against progesterone (P), aldosterone (A) and dexamethasone (DM), by displacement of: (3H)-ORG 2058 from the progestagen receptor of uterus, (3H)-A from Type I (mineralocorticoid) receptor of the kidneys and (3H)-DM from glucocorticoid receptors of the kidney (Type II) and of the liver. The various modifications introduced in the progesterone molecule led to sequences in competition potency which were either parallel or opposite in the progesterone compared to the 19 nor progesterone series. The main practical conclusion is that TX066 which is intended for use as a progestagen presents very little mineralo- and glucocorticoid activities at the receptor level, while its affinity for the progestin receptor is nearly as good as that of progesterone. The two derivatives TX045 and TX071 displayed very little or no progestagen affinity while their mineralo- and glucocorticoid potencies were between those of 19NP and TX066.