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Conceptus secretion of oestrogen on Day 11 of gestation is involved with establishment of pregnancy in the pig. Changes in oestrogen receptor (ER) protein, mRNA and cellular localization in the endometrium were evaluated during the oestrous cycle and early pregnancy of the gilt. In nonpregnant gilts, concentration of nuclear ER in the endometrium increased from Days 0 to 12 followed by a decline on Day 15 of the oestrous cycle. In pregnant gilts, changes in endometrial nuclear ER during Days 10, 12, 15 and 18 were similar to that in cyclic pigs. Analysis of endometrial ER mRNA expression did not detect any difference between cyclic and pregnant pigs between Days 10 and 15 postoestrus. Expression of ER mRNA in endometrium of cyclic and pregnant gilts was greatest on Day 10 followed by a decline on Day 15. Endometrial ER mRNA increased on Day 18 of the oestrous cycle, but remained low during pregnancy. Immunocytochemical localization of ER in the endometria of cyclic and pregnant gilts indicated that there was intense staining for ER in stromal cells and moderate to strong staining in surface and glandular epithelial cells during oestrus (Day 0) and Day 18 of the oestrous cycle. However, stromal ER staining was absent from Days 5 to 15 of the oestrous cycle and continued to be suppressed on Day 18 of pregnancy. Immunocytochemical staining of ER in the surface and glandular epithelium was readily detectable from Days 0 to 12 of the oestrous cycle and during pregnancy. Intensity of staining for ER declined in surface epithelial cells on Day 15 in both cyclic and pregnant pigs whereas positive staining for ER in glandular epithelium was absent. Staining for ER on uterine surface epithelial cells increased during pro-estrus (Day 18) of cyclic gilts but remained similar to Day 15 in pregnant gilts. Changes in endometrial ER protein, mRNA and localization in surface epithelium are consistent with a physiological role for conceptus oestrogen secretion in uterine function and maternal recognition of pregnancy in the pig.

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The role of GPIIb/IIIa antagonists in the prevention of thrombosis has gained increasing attention in recent years. 1,2 Since chronic oral administration of GPIIb/IIIa antagonists could, in principle, address myocardial infarction and stroke, the number one and number three leading causes of death in the United States, 3 intense interest has developed over the discovery of orally active GPIIb/IIIa antagonists. The peptide SK&F 107260 4 (1, depicted in Table 1), shown to contain a turn-extendedturn conformation about the critical residues (NMe)Arg-Gly-Asp, 5 was one of a series of cyclic peptide antagonists that defined a peptide pharmacophore model 6 which was employed in the design 7 of a series of 8-substituted 3-oxo-1,4-benzodiazepine GPIIb/IIIa antagonists, typified by the 8-(p-amidinophenyl)amido compounds 2 and 3. 7,8 Extensive investigations of the 8-substituted analogs have led to the discovery of several analogs which displayed oral activity but with limited oral duration of action.We have concurrently explored a series of 7-substi-