High impact information on Retrothiorphan

• This hypothesis is supported by reported crystallographic studies on related enzymes such as thermolysin and carboxypeptidase A. As expected, retro-thiorphan exhibits about the same analgesic potency as thiorphan on the hot plate and writhing tests in mice [1].
• Inhibition of neutral endopeptidase with retrothiorphan (25 nM) had no effect on BK degradation [2].
• Thiorphan [N-[(S)-2-(mercaptomethyl)-1-oxo-3-phenylpropyl]glycine] [HSCH2CH(CH2C6H5)CONHC-H2COOH] and retro-thiorphan [[[(R)-1-(mercaptomethyl)-2-phenylethyl] amino]-3-oxopropanoic acid] [HSCH2CH(CH2C6H5)NHCOCH2COOH] are isomeric thiol-containing inhibitors of endopeptidase EC 24-11 (also called "enkephalinase") [3].
• At a lower dose (10 micrograms kg-2), ANP alone or with retrothiorphan or the C-ANP receptor ligand C-ANP (4-23) did not produce any arteriolar responses, while after the combined administration of the two inhibitors, an increase in arteriolar diameter was induced [4].
• Renal clearance studies in DOCA-salt rats showed that retrothiorphan has a transient effect on renal hemodynamics, with increases in glomerular filtration and renal blood flow (RBF) and a decrease in renal vascular resistance (RVR) [5].

Biological context of Retrothiorphan

• Relationship between the inhibitory potencies of thiorphan and retrothiorphan enantiomers on thermolysin and neutral endopeptidase 24.11 and their interactions with the thermolysin active site by computer modelling [6].
• The changes in diuresis and natriuresis induced by retrothiorphan were correlated with a significant increase in urinary cyclic GMP excretion (r = 0.89, p < 0.001 and r = 0.91, p < 0.001) [5].
• Bolus or infusion of retrothiorphan also induced increases in diuresis (92 +/- 16 vs. 124 +/- 13 vs. 38 +/- 6 microliters/min) and natriuresis (10.3 +/- 2.0 vs. 12.5 +/- 1.0 vs. 5.0 +/- 1.0 mumol/min) in DOCA-salt hypertensive rats, with a maximum change at 30 min [5].
• We studied the effects of retrothiorphan, a potent and highly specific NEP inhibitor on renal function and blood pressure (BP) [5].
• Plasma ANP and hematocrit did not change after retrothiorphan, but plasma cyclic GMP increased significantly after infusion [5].

Anatomical context of Retrothiorphan

• ANP and its potentiation by retrothiorphan limited PMN adhesion to hypoxic endothelial cells and thus decreased their MMP-9 release (P<0.01) [7].

Associations of Retrothiorphan with other chemical compounds

• Enalaprilat, an ACE inhibitor, significantly prevented the rapid degradation of BK and des-Arg9-BK in all species studied, whereas retrothiorphan, a neutral endopeptidase inhibitor, and losartan, an angiotensin II type I receptor antagonist, did not affect this metabolism [8].

Gene context of Retrothiorphan

• ANP and its potentiation by retrothiorphan were able to limit elastase release, fibronectin degradation, and SMC apoptosis [7].
• METHODS AND RESULTS: ANP alone and its potentiation by retrothiorphan, the NEP inhibitor, significantly inhibited superoxide, lysozyme, and matrix metalloproteinase (MMP)-9 release by N-formyl-Met-Leu-Phe-stimulated PMNs [7].
• A stereospecific synthesis of thiorphan [N-[2(RS)-(mercaptomethyl)-1-oxo-3-phenylpropyl]glycine] and retro-thiorphan [3-[[1(RS)-(mercaptomethyl)-2-phenylethyl]amino]-3-oxopropanoic acid], two highly potent inhibitors of enkephalinase, a neutral endopeptidase involved in enkephalin metabolism, is reported [9].
• We also compared the effects of retrothiorphan in normotensive Brown-Norway kininogen-deficient rats (BN-Kat) and DOCA-salt hypertensive kininogen-deficient rats [5].

Analytical, diagnostic and therapeutic context of Retrothiorphan

• However, a separation of the diastereoisomeric mixtures of these retro-thiorphan derivatives was achieved by HPLC [9].

References