PIP: A correlation between binding to the progestin-specific uterine cytosol receptor and with well-defined facets of progesterone action was established. Structurally similar derivatives of norprogesterone and nortestosterone were compared. Binding was measured in vitro by determining their competitive effect on the progestin-tagged uterine cytosol receptor of the rabbit and mouse. Activity in vivo was measured by determining their ability to induce endometrial proliferation in the rabbit and their inhibitory effect on the estradiol-induced uterine weight increase in the mouse. Immature female Normandy rabbits, Hartley guinea pigs, immature female Swiss SPF mice, and Sprague-Dawley SPF rats were used. Groups of 5 rabbits were primed from Days 1 to 5 by daily injections of 5 mcg estradiol. Progesterone, or a test compound, was injected from Days 6 to 10. On Day 11 the rabbits were sacrificed and the endometrium prepared for histological examination. The relative potency of each steroid was compared with that of progesterone for the rabbit. Groups of 4 mice received daily injections of .09 mcg estradiol and various doses of progesterone or test compounds. These animals were sacrificed 24 hours after the last doses and their uteri excised and weighed. Antiestrogenic activity was indicated by the inhibition of uterine weight increase. The progestin specificity of the 7-8S receptor was established. The weakest competitor was progesterone. Progestins R5020, H3510, and norgestrel were highly potent. Labeled cortisol bound in the 4-S region and served as a marker. Competition studies established that 19-nor derivatives also compete for the progesterone receptor. Structural modifications of the norprogesterone and nortestosterone molecules modified results. The in vivo biological activity of all compounds was greater than the of progesterone. The introduction of 1 or 2 double binds into the 19-nor molecule decreased this somewhat. The addition of a 17 alpha-methyl substituent (H3510) to norprogesterone also decreased activity. Other modifications of the molecules also changed activity. Results of antiestrogenic activity in the mouse showed that norprogesterone was markedly more active than progesterone. Antiestrogenic activity and binding were correlated in the case of all the monoenes (norprogesterone and H3510) and denies (H3163 and R2453). A perfect correlation was observed between binding in the rabbit and the mouse for the 12 test compounds. The search for highly potent progestins involves, as an initial step, the search for a compound that binds tightly to the 7-8S receptor. In vivo extraneous factors may also become critical. Only by measuring antiestrogenic activity and progestomimetic activity in the same species can the existence, or lack of existence, of a correlation be established.