benzyloxycarbonyl-methionyl-2(s)-cyanopyrrolidine and Visceral-Pain

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.. Proizvodnye tsianopirrolidina – benziloksikarbonil-metionil-tsianopirrolidin (ZMetPrdN), benziloksikarbonil-fenilalanil-tsianopirrolidin (ZPhePrdN), tret-butil-oksikarbonil-glitsil-tsianopirrolidin (BocGlyPrdN), tret-butil-oksikarbonil-metionil-tsianopirrolidin (BocMetPrdN) – iavliaiutsia ingibitorami proliléndopeptidazy (PÉP; KF 3.4.21.26) so znacheniiami IC50 ot 2 nM do 12 nM. Soedineniia ZMetPrdN, ZPhePrdN i BocMetPrdN nariadu s vliianiem na PÉP ingibiruiut i dipeptidilpeptidazu IV (DPP-4; KF 3.4.14.5) so znacheniiami IC50 ot 1100 nM do 3200 nM. Na modeli uksusnykh korcheĭ u mysheĭ vse izuchaemye soedineniia proiavliaiut antinotsitseptivnye svoĭstva, odnako tol'ko proizvodnye tsianopirrolidina s aromaticheskimi zamestiteliami ZMetPrdN i ZPhePrdN snizhaiut ostruiu ékssudativnuiu vospalitel'nuiu reaktsiiu u zhivotnykh. Pri étom v syvorotke krovi mysheĭ cherez tri chasa posle induktsii vospaleniia izuchaemye proizvodnye tsianopirrolidina povyshaiut aktivnost' PÉP i kompensatorno snizhaiut aktivnost' DPP-4. Takim obrazom, odin iz komponentov mekhanizma realizatsii antinotsitseptivnykh i antiékssudativnykh svoĭstv izuchaemykh proizvodnykh tsianopirrolidina, ochevidno, obuslovlen sposobnost'iu soedineniĭ okazyvat' vliianie na PÉP.

Topics: Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Inflammation; Methionine; Mice; Prolyl Oligopeptidases; Pyrrolidines; Serine Endopeptidases; Serine Proteinase Inhibitors; Visceral Pain