Effect of cyanopyrrolidine derivatives on the activity of prolylendopeptidase, acute exudative inflammation and visceral pain in mice

Abstract

Cyanopyrrolidine derivatives benzyloxycarbonyl-methionyl-cyanopyrrolidine (ZMetPrdN), benzyloxycarbonylphenylalanyl- cyanopyrrolidine (ZPhePrdN), tert-butyl-hydroxycarbonyl-glycyl-cyanopyrrolidine (BocGlyPrdN), tert-butyl-hydroxycarbonyl-methionyl-cyanopyrrolidine (BocMetPrdN) are inhibitors of prolylendopeptidase (PREP; EC 3.4.21.26) with an IC50 of 2 nM to 12 nM. ZMetPrdN, ZPhePrdN and BocMetPrdN additionally inhibited dipeptidyl peptidase IV (DPP-4; EC 3.4.14.5) with an IC50 of 1100 nM to 3200 nM. All the compounds have antinociceptive properties in the acetic acid writhing test in mice. But only cyanopyrrolidine derivatives with aromatic substituents decrease exudative inflammation. The cyanopyrrolidine derivatives also increase PREP activity and compensatorily reduce DPP-4 activity in the serum of mice three hours after the induction of inflammation. Thus, cyanopyrrolidine derivatives exhibit antinociceptive and antiexudative properties in part via their effect on PREP.

Low-affinity NMDA receptor antagonist hemantane in a topical formulation attenuates arthritis induced by Freund’s Complete Adjuvant in rats

“…26 In acetic acid-induced peritonitis in mice, intraperitoneal injections with hemantane reduced increased phospholipase A2 (PLA2) activity but did not affect the level of COX-2. 27 The PLA2 family consists of Ca2 + -dependent secretory enzymes that trigger various cell-signaling events in different mammalian tissues, 28 , 29 therefore the effect of hemantane on PLA2 activity in peritoneal exudates of mice with acetic acid-induced peritonitis could be explained by a decrease in intracellular concentration of Ca2 + due to the blockade of NMDA receptors. 30 , 31 Localizations of NMDA receptors include the central and peripheral nervous system, 32 in particular in the enteric nervous system, 33 , 34 but also lymphocytes.…”