Side chain methyl substitution in the delta-opioid receptor antagonist TIPP has an important effect on the activity profile.

The delta-opioid antagonist H-Tyr-Tic-Phe-Phe-OH (TIPP-OH) or its C-terminal amide analogue was systematically modified topologically by substitution of each amino acid residue by all stereoisomers of the corresponding beta-methyl amino acid. The potency and selectivity (delta- vs mu- and kappa-opioid receptor) were evaluated by radioreceptor binding assays. Agonist or antagonist potency were assayed in the mouse vas deferens and in the guinea pig ileum.

Conformationally constrained deltorphin analogs with 2-aminotetralin-2-carboxylic acid in position 3.

Two approaches to the design of very active and highly selective delta opioid peptides were used to obtain new deltorpin analogs with altered hydrophobic and stereoelectronic properties. Deltorphin I and II analogs were synthesized involving the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 2-aminotetralin-2-carboxylic acid (Atc) instead of Phe in the message domain. The peptides were agonists in the subnanomolar range in the MVD assay and in the micromolar or higher range in the GPI assay, showing a very high selectivity for delta receptors.

Conformational restriction of Tyr and Phe side chains in opioid peptides: information about preferred and bioactive side-chain topology.

The side chain of Tyr and Phe was fixed into the gauche(-) or gauche(+) conformation by using the Tic Htc structures, and into the trans conformation by using an aminobenzazepine-type (Aba) structure. When incorporated into dermorphin or deltorphin II, the Tic and Htc analogues all showed a large decrease in both mu and delta affinities and activities. Fixation of Phe(3) in the trans rotamer resulted in a large increase in delta affinity in the dermorphin analogue, whereas in the [Aba(3)-Gly(4)] deltorphin II analogue, good delta affinity is maintained despite the removal of the Glu side chain.

Comparing conformations at low temperature and at high viscosity. Conformational study of somatostatin and two of its analogues in methanol and in ethylene glycol.

The influence of low temperature and high viscosity on the conformation of somatostatin and two of its analogues was investigated by 1H NMR in solution. The conformation of native somatostatin, a cyclic octapeptide agonist DC13-116 and a linear octapeptide agonist were compared in ethylene glycol at 303 K and in methanol at low temperature. The first goal of this study was to investigate if either low temperature or high viscosity is the more important for the reduction of the conformational freedom.

Conformational study of cyclosporin A in acetone at low temperature.

The conformation of cyclosporin A (CsA), an undecapeptide with seven N-methylated amino acids, was studied in acetone at 193 K. Previous studies of the conformation of CsA in different solvents, in the cyclosporin-cyclophilin complex and in complexes with LiCl showed that the conformation of the free and the bound CsA are different. Differences were observed at the conformation of the MeLeu9-MeLeu10 peptide bond, which is cis in solution and trans in the complex, and in the orientation of the amide protons and the N-Me groups.

Conformational study of a series of somatostatin analogues with antitumor and/or GH inhibitory activity.

A series of somatostatin analogues with varying activities have been studied by 1H NMR in CD3OH at low temperature in order to find a possible structural explanation for the differentiation of biological activities. In somatostatin analogues with GH release inhibitory activity a beta-turn/beta-sheet backbone conformation is present, which is shown to be characteristic of somatostatin-derived peptides exhibiting this biological activity. On the other hand, among the analogues with antitumor activity, a deviation from these typical structural features is clearly observed, but not general conformational model can be proposed.

Dermorphin tetra- and heptapeptide analogues containing a [3,4] amide bond replacement by a carbon-carbon double and single bond.

Seven dermorphin hepta- and tetrapeptide analogues containing [3,4] amide bond replacement by a carbon-carbon double and single bond were prepared. 1H NMR studies of the pseudoheptapeptide in DMSO indicate the presence of extended conformations with stacking of the side chains in the N-terminal part and an inverse gamma-turn around Ser7 in the conformational equilibrium. The binding data show that the affinity of the analogues for the mu-receptor is only slightly diminished in the D-Ala2 series and is more affected in the D-Arg2 series.

Active transport of L-sorbose and 2-deoxy-D-galactose in Saccharomyces fragilis.

Sorbose and 2-deoxy-D-galactose are taken up in Saccharomyces fragilis by an active transport mechanism, as indicated by the energy requirement of the process and the accumulation of free sugar against the concentration gradient. There are no indications for transport-associated phosphorylation as mechanism of energy coupling with these two sugars. The measured sugar-proton cotransport and the influx inhibition by uncouplers suggest a chemiosmotic coupling mechanism.

Transport of 2-deoxy-D-galactose in Saccharomyces fragilis.

2-Deoxy-D-galactose (dGal) transport in Saccharomyces fragilis is characterized by energy requirement and accumulation of the free sugar against a concentration gradient, indicating active transport. Besides free sugar dGal-1-phosphate, UDP-dGal and a trehalose-like derivative were found inside the cells. The accumulation of the phosphorylated derivatives was balanced by a concomitant decrease of ATP, orthophosphate and polyphosphates.

Transport-associated phosphorylation of 2-deoxy-D-glucose in Saccharomyces fragilis.

2-Deoxy-D-glucose transport and metabolism was studied in Saccharomyces fragilis. Inside the cells four phosphorylated and three non-phosphorylated derivatives were found and identified. Accumulation of phosphorylated 2-deoxyglucose derivatives was balanced by a concomitant decrease of cellular ATP, orthophosphate and polyphosphates.