ABSTRACT
BACKGROUND: Activity of nomegestrol acetate (NOMAC), levonorgestrel (LNG), drospirenone (DRSP), dienogest (DNG) and progesterone on human steroid receptor transactivation was investigated. Ovulation inhibition by NOMAC, LNG and progesterone was tested. STUDY DESIGN: The progestogen receptor profile was determined in Chinese hamster ovary cells transfected with human progesterone B (PRB), androgen, estrogen (ER(α) and ER(ß)), glucocorticoid (GR) and mineralocorticoid (MR) receptors, respectively. Ovulation inhibition was tested in rats and monkeys. RESULTS: Agonistic potency rankings for PRB were LNG=NOMACâ«progesteroneâ«DRSP>DNG. No antagonistic activity at PRB was observed. Only LNG had androgenic activity. Antiandrogenic potency rankings were LNGâ«NOMAC>progesterone>DNG>DRSP. All agents were devoid of activity at ER(α), ER(ß) and GR. Only progesterone, DRSP and LNG had anti-MR activity. The NOMAC dose inhibiting ovulation at 50% ranged from 0.14 mg/kg (monkey) to 1.25 to 5.0 mg/kg (rat). CONCLUSION: Nomegestrol acetate is a selective progestogen and a potent inhibitor of ovulation in the rat and monkey.
Subject(s)
Megestrol/analogs & derivatives , Ovulation/drug effects , Progesterone Congeners/pharmacology , Receptors, Steroid/agonists , Animals , CHO Cells , Cricetinae , Cricetulus , Female , Humans , Macaca fascicularis , Megestrol/pharmacology , Rats , Rats, Wistar , Receptors, Steroid/antagonists & inhibitorsABSTRACT
We have developed a new class of progesterone receptor agonists having a tetracyclic dibenzo-oxazepine structure 1. In this paper, the synthesis and structure-activity relationships of this new class are described. This work led to the identification of potent progesterone agonists up to 1 nM activity. Substitution at positions 6, 7 and 1 has proven to be crucial for activity, indicating that probably these positions are involved in important interactions with the receptor.
Subject(s)
Oxazepines/chemistry , Oxazepines/pharmacology , Receptors, Progesterone/agonists , Acetamides , Binding Sites , Fluoroacetates , Models, Molecular , Progesterone/chemistry , Structure-Activity Relationship , Trifluoroacetic Acid/chemistryABSTRACT
The Slc26 family is a conserved family of anion transporters. In the human, their physiological relevance was highlighted with the discovery of pathogenic mutations in several Slc26 transporters that lead to distinctive clinical disorders (Pendred syndrome, deafness, diastrophic dysplasia, congenital chloride diarrhoea) that are related to the specific distribution of these genes. We previously identified TAT1 as a new family member (Slc26A8), very specifically expressed in male germ cells in both the human and the mouse. To investigate Tat1 function in the male germline, we generated mice with a targeted disruption of the Tat1 gene. Heterozygous and homozygous Tat1 mutant mice were indistinguishable from wild-type littermates concerning survival rate, general appearance and gross behaviour; however, Tat1 null males were sterile due to complete lack of sperm motility and reduced sperm fertilization potential. Ultra-structural analysis revealed defects in flagellar differentiation leading to an abnormal annulus, disorganization of the midpiece-principal piece junction, hairpin bending of the sperm tail with disruption of the axial structures, and abnormal mitochondrial sheath assembly. While ATP levels were normal, ATP consumption was strongly reduced in Tat1 null spermatozoa. Interestingly, Tat1 is located at the annulus, a septin-based circular structure connecting the midpiece to the principal piece. Altogether, our results indicate that Tat1 is a critical component of the sperm annulus that is essential for proper sperm tail differentiation and motility.