Cyclic tetrapeptides with sequences related to HC toxin. Conformations and cation binding

Peptides with sequences related to HC toxin (cyclo(l Ala-d Ala-l -Aoe-d Pro)) can adopt a conformation locked by three γ turns. A “structure — spectroscopy characteristics” relationship is proposed. These peptides can complex Mg++ cations and the binding is accompanied by a transconformation of the peptide backbone. The relevance with the biological activity of the toxin is discussed.     

Mothers'' Perceptions of Their Neonates'' In-hospital Transfers from a Neonatal Intensive-Care Unit

This study explored mothers' perceptions of their neonates' in-hospital transfers from a neonatal intensive-care unit. A convenience sample of 15 mothers was selected, and the researchers interviewed each mother once within a week after her neonate's transfer. Three themes emerged from the data: (1) the mothers expressed feelings of relief accompanied by concern, fear of the unknown, and feelings of alienation; (2) the mothers depended on familiar things and people; and (3) the mothers experienced feelings of helplessness. The mothers' perceptions of their preparation for transfer and continuity of care were mainly negative.     

Evaluation of biological activities of new LH-RH antagonists (T-series) in male and female rats

A series of new highly potent LH-RH antagonists (T-series) has been synthesized in our laboratory. Among these analogs, antagonists [Ac-d -Nal(2), d -Phe(4Cl)². d -Pal(3)³, d -Lys(A₂pr(Car)₂)⁶, d -Ala¹⁰LH-RH (T-140); [Ac-d -Nal(2)¹, d -Phe(4Cl)², d -Pal(3)³, d -Lys(A₂pr(Ac)₂)⁶, d -Ala¹⁰]LH-RH (T-148); [Ac-d -Nal(2)¹, d -Phe(4Cl)², d -Pal(3)³, d -Lys(A₂pr(For)₂)⁶, d -Ala¹⁰)]LH-RH (T-151) and [Ac-d -Nal(2)¹, d -Phe(4cl)², d -Pal(3)³, d -Lys(A₂bu(For)₂)⁶, d -Ala¹⁰]LH-RH (T-159) were the most powerful. Antagonists T-140, T-148 and T-151 produced a complete blockade of ovulation in normal cycling rats at a dose of 1.5 μg/rat and antagonist T-159 at a dose of only 0.75 μg/rat. The inhibitory effects of compounds T-148, T-151 and T-159 on gonadotropin and sex steroid secretion were investigated in male and female rats. To determine their effect on LH levels in castrated male and ovariectomized female rats, T-148, T-151 and T-159 were injected subcutaneously in doses of 0.625 and 2.5 μg/rat. Blood samples were taken at different intervals for 48 h. All three compounds at either dose caused a significant (P< 0.01) decrease in LH levels for more than 6 h. Significant (P <0.01) inhibition of LH lasted for more than 24 h following a dose of 2.5 μg sc of all 3 antagonists in both male and female rats. Serum FSH levels were also suppressed significantly for more than 48 h in castrated male rats by all three antagonists at a dose of 5 μg/rat sc. Serum testosterone levels were measured in intact male rates injected with antagonists T-148, T-151 and T-159 in doses of 50 and 100 pg sc. Both doses produced a dramatic fall in testosterone (P<0.01) to castration levels 6 h after injection. The inhibition of serum testosterone lasted for more than 48 h, but only 100 μg of T-148 maintained testosterone in the castration range for more than 48 h. Antagonists T-148, T-151 and T-159 injected at a dose of 100 μg to intact female rats reduced serum estradiol levels significantly (P<0.01) for more than 48 h, as compared to control animals. In the cutaneous anaphylactoid test (CAT), T-148, T-151 and T-159 proved to have very low histamine releasing activities. These data demonstrate a high efficacy of these new LH-RH antagonists in suppressing the pituitary-gonadal axis in male and female rats. These LH-RH antagonists could possibly be used for treatment of sex-hormone sensitive cancers and other disorders and conditions, in which a reduction in circulating sex steroids would be beneficial.     

New antagonists of LHRH II. Inhibition and potentiation of LHRH by closely related analogues

Modifications of the previously described LHRH antagonists, [Ac-d -Nal(2)¹, d -Phe(4Cl)², d -Trp³, d -Cit⁶, d -Ala¹⁰]LHRH and the corresponding d -Hci⁶ analogue, have been made to alter the hydrophobicity of the N-terminal acetyl-tripeptide portion. Substitution of d -Trp³ with the less hydrophobic d -Pal(3) had only marginal effects on the antagonistic activities and receptor binding potencies of the d -Cit/d -Hci⁶ analogues, but it appeared to further improve the toxicity lowering effect of d -Cit/d -Hci⁶ substitution. Antagonists containing d -Pal(3)³ and d -Cit/d -Hci⁶ residues, i.e. [Ac-d -Nal(2)¹, d -Phe(4Cl)², d -Pal(3)³d -Cit⁶, d -Ala¹⁰]LHRH (SB-75) and [Ac-d -Nal(2)¹, d -Phe(4Cl)², d -Pal(3)³, d -Hci⁶, d -Ala¹⁰]LHRH (SB-88), were completely free of the toxic effects, such as cyanosis and respiratory depression leading to death, which have been observed in rats with the d -Trp³, d -Arg⁶ antagonist and related antagonists. Replacement of the N-acetyl group with the hydrophilic carbamoyl group caused a slight decrease in antagonistic activities, particularly in vitro. Introduction of urethane type acyl group such as methoxycarbonyl (Moc) or t-butoxycarbonyl (Boc) led to analogues that showed LHRH-potentiating effect. The increase in potency induced by these analogues, e.g. [Moc-d -Nal(2)¹, d -Phe(4Cl)², d -Trp³, d -Cit⁶, d -Ala¹⁰]LHRH and [Boc-d -Phe¹, d -Phe(4Cl)², d -Pal(3)³, d -Cit⁶, d -Ala¹⁰]LHRH, was 170-260% and persisted for more than 2 h when studied in a superfused rat pituitary system.     

Enzymatic peptide synthesis in organic solvent mediated by gels of copolymerized acrylic derivatives of α-chymotrypsin and polyoxyethylene

Copolymers of acrylated derivatives of α-chymotrypsin and polyethylene glycol (PEG) have been prepared and used as biocatalysts for the synthesis of model peptides in organic solvent containing a low quantity of water. Other peptide couplings have been tried to point out the chemico- and stereoselectivity and examples of segment couplings are given.