PubMed · 9010340
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1996. Progestins: present and future.. https://doi.org/10.1016/s0960-0760(96)00183-5
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Although sex steroids and steroid converting enzymes have been found in echinoids, the relationship between steroids and reproduction has not been demonstrated. On days 0, 4, 8, 16, 32, and 48 of feeding, the gonads of previously starved Lytechinus variegatus were excised and incubated with [3H]androstenedione for 0.5 h to determine if changes in steroidogenic capacity are correlated with gonadal growth. Total rates of androstenedione conversion in the testes and ovaries increased significantly during feeding. In addition, the types and relative quantities of metabolites synthesized varied, suggesting that androstenedione metabolism is influenced by nutritional status. Both testes and ovaries synthesized testosterone, 5alpha-androstane-3alpha,17beta-diol, and 5alpha-androstane-3beta, 17beta-diol (5alpha-adiols), 5alpha-androstanedione, epiandrosterone, and androsterone on all days of feeding. In the testes, the relative quantities of testosterone and 5alpha-adiols increased greatly on day 4 of feeding. In contrast, in the ovaries testosterone synthesis was not detectable on day 4, although the relative quantities of 5alpha-adiols increased threefold. The sex-specific changes in the synthesis of these metabolites reflect a shift in the metabolic pathway indicated by changes in the relative enzyme activity indices for 5alpha-reductase (5alpha-R) (necessary for the synthesis of 5alpha-reduced androgens) and 3alpha/beta-hydroxysteroid dehydrogenase (3alpha/beta-HSDs, necessary for the synthesis of 3alpha- or 3beta-hydroxylated androgens). In both testes and ovaries the relative activities of 5alpha-R and 3alpha/beta-HSD increased on day 4 of feeding. The physiological significance of changes in androstenedione metabolism may be associated with the initiation of biosynthetic processes associated with gametogenesis.
A series of digitalis-like compounds, with the lactone ring shifted from the original position through a spacer or replaced by a series of guanylhydrazone substituent-bearing chains, was synthesized and evaluated for inhibition of Na+,K(+)-ATPase and for inotropic activity. The highest Na+,K(+)-ATPase inhibition (IC50) and inotropic activity (EC50) were reached with the vinylogous guanylhydrazone 5 where a cardenolide-like polarized alpha,beta-unsaturated system and a basic guanidino group were both present at the 17 beta-position; for this compound IC50 and EC50 values were comparable to or higher than those of Thomas' parent guanylhydrazone 1, digitoxigenin, and digoxin. A substantial improvement of the desired positive inotropic activity versus the toxic arrhythmogenic concentration was not reached within this series; only a slightly better therapeutic index can be envisaged for compounds 5 and 4, even though, for the latter, to the detriment of potency, presumably because of a weaker interaction with the receptor, due to the lack of a cardenolide-like polarized system.
The effects of the transglutaminase-synthesized polyamine derivatives of Substance P (SP) have been further characterized by their ability to contract in vitro the rat portal vein strip (RPV), a pharmacological preparation particularly rich in NK-3 receptors. The effects of selective agonists of NK-1, NK-2 and NK-3 receptors [Sar9,Met(O(2))11]SP, beta-Ala8 NKA(4-10), and senktide respectively, were also evaluated by measuring RPV concentration-response curves. Peptide [GR-82334 (NK-1) and MEN-10,376 (NK-2)] and nonpeptide [WIN 51,708 (NK-1) and SR 142801 (NK-3)] NK receptor antagonists were used to confirm the participation of the different NK receptors to contractile response. Our results demonstrated that the spermine derivative of SP (Spm-SP), previously shown to be unable to recognize NK-1 and NK-2 receptors in some bioassays, contracts RPV (EC50 = 588 nM) better than the native neuropeptide (EC50 = 1120 nM). A pretreatment with thiorphan, an inhibitor of neutral endopeptidases, significantly reduced such a difference. While this inhibitor shifts the SP concentration-response curves to the left (EC50 = 720 nM) the action of Spm-SP and [Sar9,Met(O(2))11]SP were completely thiorphan-resistant. In the absence of thiorphan we found the following rank order of potency: senktide > > beta-Ala8 NKA(4-10) > [Sar9,Met(O(2))11]SP = Spm-SP > SP. Among the mentioned NK receptor antagonists, only the selective NK-3 receptor antagonist, SR 142801, shifted to the right Spm-SP and [Sar9,Met(O(2))11]SP concentration-response curve, showing pKB values of 5.84 and 5.88, respectively. Therefore, the reported results suggest that the introduction of a Spm moiety into the SP alters the parent peptide molecule by increasing its affinity for NK-3 receptors and/or by preventing its degradation by some proteolytic enzymes.