Molecular docking of opiates and opioid peptides, a tool for the design of selective agonists and antagonists, and for the investigation of atypical ligand-receptor interactions.

In the last years, molecular docking emerged as a powerful tool to investigate the interactions between opioid ligands and their receptors, thus driving the design and development of new selective agonists or antagonists of therapeutic interest. This review especially covers the most representative and recent comparative molecular docking analyses of structurally related compounds, as well as of agonists and antagonists within the active and inactive states of the receptors. The comparative analyses gave important information on the structural determinants responsible for the affinity and selectivity of the ligands, and defined the features responsible for the activation of the receptors. A special section is dedicated to the analyses of recently discovered, unusual agonists lacking of the tyramine pharmacophore, such as Salvinorin A, and the cyclopeptides which comprise the D-Trp-Phe pharmacophoric motif. For the atypical structure of these compounds, the docking proved to be essential to disclose how they interact with and activate the receptors.

Computerized analysis of heart rate in fetuses from mothers under levothyroxin treatment.

OBJECTIVE: To investigate fetal heart rate (FHR) of fetuses whose mothers are under levothyroxin treatment for chronic hypothyroidism. STUDY DESIGN: Sixty women under chronic therapy with levothyroxin and 180 controls at 37-39 weeks' gestation were studied by Sonycaid Sistem 8002(R) computerized cardiotocography (cCTG) for 30 min. cCTG parameters were expressed as mean and SD and the differences tested for statistics by Student t-test. Furthermore, cCTG parameters were related to levothyroxin dose by regression analysis. Significance was assessed at p < 0.05. RESULTS: Computerized cardiotocographic tracings of fetuses from mothers under levothyroxin treatment revealed: significant reduction of baseline FHR (130.1 +/- 9.47 vs. 134.9 +/- 4.68 bpm); increased number of FHR decelerations greater than 20 bpm (0.2 +/- 0.41 vs. 0.05 +/- 0.22); reduction of body movements per hour (6.68 +/- 11.72 vs. 10.65 +/- 11.74); and increased uterine contraction peaks (5.15 +/- 4.69 vs. 2.7 +/- 2.57). Those fetuses also showed significantly reduced neonatal weight (2668.2 +/- 766.65 vs. 3215.44 + 523.88 g) and lower 1-min Apgar score (8.6 +/- 0.95 vs. 9.3 +/- 1.11). Regression analysis showed a significant correlation between levothyroxin dose and baseline FHR (r = 0.60; p < 0.0001) and fetal body movements per hour (r = 0.52; p < 0.0001), and an inverse relationship with uterine contraction peaks (r = -0.35; p < 0.006), whilst no correlation was found with the number of FHR decelerations greater than 20 bpm. CONCLUSIONS: Maternal hypothyroidism and levothyroxin treatment influence FHR and cCTG is a sensible tool to reveal that influence.

Unusual amino acids: synthesis and introduction into naturally occurring peptides and biologically active analogues.

This review covers our recent advances in the synthesis of unusual amino acids in optically pure form, and their introduction into naturally occurring peptides with specific biological properties, or into modified bioactive peptides, aiming to obtain analogues displaying enhanced performances in term of activity, bioavailability and resistance to enzymatic hydrolysis.

NMR investigations on boron complexes in the conjugate addition on alpha,beta-unsaturated imides.

[reaction: see text]. The 1,4-addition of O-benzylhydroxylamine to alpha,beta-unsaturated imide 1 in the presence of BF3.Et2O proceeds with the preferential attack of the nucleophile on the Cbeta-re face. To explain this unexpected reactivity 1H, 13C, and 11B NMR investigations have been carried out on the boron-imide complex, which show the presence of an S-cis imide chain conformation.

A new selective synthesis of the Ile-allo-Thr-Gly tripeptide fragment of lysobactin.

[formula: see text] trans-Aziridine-2-carboxylic acid derivatives are useful intermediates for the synthesis of threonine or allo-threonine through ring expansion and SN2 displacement, respectively. We describe here the preparation of the Ile-allo-Thr-Gly 11 fragment of Lysobactin via the aziridine 9 intermediate.

Synthesis and binding activity of endomorphin-1 analogues containing beta-amino acids.

Endomorphin-1 (Tyr-Pro-Trp-PheNH2) has been proposed as the most potent endogenous ligand of the mu-opioid receptors. In this paper, we describe the synthesis of some endomorphin-1 based tetrapeptides in which a residue of the sequence Tyr-Pro-Trp-PheNH2 is replaced by the corresponding beta-isomer. These novel peptides showed different affinities for the opioid receptors labeled with [3H]-DAMGO in rat brain membranes, depending on the beta-amino acid. In particular, the tetrapeptide containing beta-Pro (Tyr-beta-(R)-Pro-Trp-PheNH2) displayed a higher affinity than endogenous endomorphin-1, as revealed by their Ki values (0.33 and 11.1 nM, respectively).