Evidence of a peptide backbone contribution toward selective receptor recognition for leucine enkephalin thioamide analogs.

The in vitro opioid activities of a series of leucine enkephalin analogs containing a thioamide linkage in place of the peptide bond at various positions of the backbone were determined in mu- and delta-receptor-selective bio- and binding-assays. Thioamide substitution in the 1-2 position resulted in an inactive compound, whereas the same modification in the 2-3 and 4-5 position produced potency enhancement. Most interestingly, the 2-3 modified analog showed a 3 to 5 times higher preference for delta- over mu-receptors than natural leucine enkephalin. These results suggest that subtle backbone modifications can have a profound effect on receptor affinity and selectivity of biologically active peptides.

The geometry of the thiopeptide unit.

The structure of the modified dipeptide Z-Glyt-Gly-OBzl is reported with special emphasis on the linear and angular dimensions of the thiopeptide unit. It is shown that, except for the differences between the carbonyl and the thioacyl bond lengths, there are no significant differences between the oxopeptide and the thiopeptide unit.

The destruction of N-nitrosamides with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiodiphosphetane-2,4-disulfide. Attempts to nitrosate thioamides.

The reaction between N-nitrosamides and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (LR) at low temperature (20-50 degrees C) gives the corresponding thioamides as the main products. In the reaction between N-nitroso-2-pyrrolidone and LR, dihydro-2-(3H)-thiophenone (III) is also isolated. Mechanistic considerations for the formation of III are presented. The nitrosation of thiono compounds gives the corresponding oxo analogues. N-Nitroso-2-pyrrolidone is obtained after nitrosation of 2-pyrrolidinethione. A kinetic investigation of this reaction has been performed using the theory of consecutive reactions with 2-pyrrolidone as an intermediate. The rate constants for these two reactions are found to be k1 = 0.055 s-1 for the formation of 2-pyrrolidone, using a first order plot of the change of 2-pyrrolidinethione; for the formation of N-nitroso-2-pyrrolidone, the rate constant obtained by computer simulation is k2 = 0.032 mol(-1)1 s-1.

The reaction of N-nitroso compounds with 2,4-bis (4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide. New aspects of the destruction of the N-nitroso function.

In connection with work on 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (I), used for thiation of carbonyl compounds, different kinds of compounds with semipolar bondings have been reacted with I, especially C- and N-nitroso compounds. C-Nitroso compounds give azoxy and azo compounds. N-Nitroso compounds give new phosphorus ring systems, depending on the starting material, and the N-nitroso function is destroyed. An elimination of HNO has been observed where there was resonance stabilization in the imine formed.