Modification of the Phe 3 aromatic moiety in delta receptor-selective dermorphin/deltorphin-related tetrapeptides Effects on opioid receptor binding

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72346/1/j.1399-3011.1992.tb01449.x.pd

Straightforward and Diastereoselective Synthesis of Tetrafunctionalized Thiol Synthons for the Design of Metallopeptidase Inhibitors

International audienceTetrafunctionalized thiol-containing synthons with different side-chains have been prepared with good yields by a straightforward diastereoselective and general methodology. The key step of the synthesis consisted of a tandem reduction and Wittig–Horner reaction, which conserved the stereochemistry of the starting material. The method was generalized to different side-chains, allowing synthons for designing inhibitors of various classes of zinc metallopeptidases to be easily obtained

Synthesis of 2(S)-benzyl-3-[hydroxy(1?(R)-amino ethyl)phosphinyl]propanoyl-L-3-[125I]-iodotyrosine: a radiolabelled inhibitor of aminopeptidase N

International audience2(S)‐benzyl‐3‐[hydroxy(1′(R)‐aminoethyl)phosphinyl]propanoyl‐L‐3‐[125I]‐iodo tyrosine was prepared from 1(R)‐(N‐benzyloxycarbonylamino)ethylphosphinic acid in a six step synthesis. This new iodinated compound, which is a highly efficient aminopeptidase N inhibitor (Ki=0·95 nM), can be used for complete characterization of the biochemical and pharmacological properties of aminopeptidase N and its in vivo inhibition. A high radiochemical purity was obtained with a specific activity of 217 Ci/mmol at the end of the synthesis. Copyright © 2000 John Wiley & Sons, Ltd

Differences in transition state stabilization between thermolysin (EC 3.4.24.27) and neprilysin (EC 3.4.24.11).

Important homologies in the topology of the catalytic site and the mechanism of action of thermolysin and neprilysin have been evidenced by site-directed mutagenesis. The determination of differences in transition state stabilization between these peptidases could facilitate the design of specific inhibitors. Thus, two residues of thermolysin which could be directly (Tyr157) or indirectly (Asp226) involved in the stabilization of the transition state and their putative counterparts in neprilysin (Tyr625 and Asp709) have been mutated. The results show that Tyr157 is important for thermolysin activity while Tyr625 has no functional role in neprilysin. Conversely, the mutation of Asp226 induced a slight perturbation of thermolysin activity while Asp709 in neprilysin seems crucial in neprilysin catalysis. Taken together these data seem to indicate differences in the transition state mode of stabilization in the two peptidases