Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) activate the LH receptor/cyclic AMP (cAMP) signaling pathway to induce ovulation. As an alternative to parenterally administered hCG to treat anovulatory infertility, orally active low molecular weight (LMW) LHR agonists have been developed at Organon. In this paper, we present the mechanism of action of a prototypic, nanomolar potent and almost full LHR agonist, Org 43553. Org 43553 interacts with the endodomain of the LHR, whereas LH acts via the N-terminal exodomain. LH stimulates the cAMP pathway with an EC50 of 35 pM, but this stimulation is not antagonized by simultaneous incubation with Org 43553. At nanomolar concentrations, LH also stimulates phospholipase C (PLC), but Org 43553 is hardly able to do so. In contrast, Org 43553 inhibits LH-induced PLC (IC50 approximately 10 nM). While Org 43553 stimulates dissociation of [125I]hCG from the LHR and reduces [125I]hCG binding, LH reduces specific [3H]Org 43553 binding. We conclude that Org 43553 is a signaling-selective, allosteric LHR agonist. We hypothesize that Org 43553 and LH induce a similar LHR conformation necessary for activating adenylyl cyclase, which initiates most, if not all, physiological responses of LH.

Pregnancy in pill form? The identification of low molecular weight (LMW) agonists for receptors normally triggered by high molecular weight (HMW) endogenous ligands is a great challenge for medicinal chemists. Thienopyrimidines and thienopyridines of general structures 1 and 2, respectively, are the first orally active LMW agonists for the G‐protein‐coupled luteinizing hormone receptor, which is responsible for ovulation induction. The LMW agonists display micromolar to nanomolar potencies and in vivo ovulation induction could be demonstrated in mice after oral administration. Thus, these compounds mimic the mode of action of the endogenous HMW glycopeptidic luteinizing hormone.

We have isolated and purified a glycoprotein from the corpuscles of Stannius (CS) of trout, which we consider hypocalcin (also called teleocalcin), the major hypocalcemic hormone of fish. This product is present in relatively large amounts in the CS of several species (i.e., European eel, tilapia, goldfish, and carp). Hypocalcin is typically released from the CS in response to an experimentally induced increase of the blood calcium concentration. Ultrastructural observations show that after this treatment the type I cells, reportedly the hypocalcin-producing cell type of the CS, are almost completely degranu lated. The isolated glycoprotein has an apparent molecular weight of 54 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. This molecule appears sus ceptible to breakdown and is recovered upon concanavalin-A affinity chromatography as a 41 kDa product. Reducing agents such as mercaptoethanol or dithiothreitol employed, e.g., during standard electrophoretic techniques or during amino acid sequence analysis, allow only the recovery of 28 or 18 kDa products. Evidence is given that the 54 and 41 kDa products are dimer molecules, with the 28 and 18 kDa products as their respective monomeric constituents. The sequence of the first 33 N-terminal amino acids of these products and the composition of the sugar component are presented. © 1988 Academic Press, inc.C o r p u s c le s o f S ta n n iu s (C S) are endocrine glands characteristic of holostean and teleostean fish. Since their dis covery by Stannius (1839) a large body of histological research on the CS of many fish species has been carried out (Bauchot, 1953;Krishnamurthy, 1976;Krishnamurthy and Bern, 1969;. CS produce a factor that prob ably is the predom inant hypocalcem ic hormone in fish. Removal of the glands results in a strong increase in blood calcium concentration (e.g., Fontaine, 1964) that is reversed by reim plantations of CS or injections of CS tissue homogenates (Fon taine, 1967;Pang, 1973; Pang et al.f 1973 Pang et al.f , 1974. Since the gills probably form the major site of calcium exchange between fish and water, inhibition of branchial cal cium uptake may underlie hypocalcemic control (Fenwick, 1987; Fenwick, 1977, 1979).There exists immunological resemblance between the hypocalcemic principle of CS and the parathyroid hormone (PTH) of the higher vertebrates (Lopez et at., 1981(Lopez et at., , 1984 Milet et cil., 1982). Moreover, the CS hypocalcemic principle has similar bioac tivity as PTH in mammalian and fish bioas says (Lafeber et cd., 1986a, c;Milet et al., 1980; V erbost et cil., 1986; W endelaar Bonga et al.y 1986 . The fact that type I cells respond to changes in external calci um has led many researchers to postulate that these cells produce the hvpocalcemic factor (M eats et al., 1978; W endelaar Bonga ei al., 1980;.In 1976 Krishnamurthv sumzested, on the basis of histological staining by periodic acid Schiff reagent, that the type 1 cells contain a glycoprotein. In 1978 Ma and Copp isolated a 3 ...

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