Therapeutic Effect of Novel Cyanopyrrolidine-Based Prolyl Oligopeptidase Inhibitors in Rat Models of Amnesia.

Nikolay N Zolotov,Igor A Schepetkin,Mark T Quinn,Tatyana A Voronina,Andrei I Khlebnikov,Irina V Krylova,Vladimir F Pozdnev

doi:10.3389/fchem.2021.780958

Abstract

Prolyl oligopeptidase (POP) is a large cytosolic serine peptidase that is altered in patients with Alzheimer’s disease, Parkinsonian syndrome, muscular dystrophies, and other denervating diseases. Thus, POP may represent a relevant therapeutic target for treatment of neuropsychiatric disorders and neurodegenerative diseases. Here, we report the characterization of five novel cyanopyrrolidine-based compounds (BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, CbzGlnPrdN, and CbzAlaPrdN) and show that they are potent inhibitors of POP and are predicted to penetrate the blood-brain barrier (BBB). Indeed, we show that CbzMetPrdN penetrates the rat BBB and effectively inhibits POP in the brain when administered intraperitoneally. Furthermore, molecular modeling confirmed these compounds likely inhibit POP via interaction with the POP catalytic site. We evaluated protective effects of the cyanopyrrolidine-based POP inhibitors using scopolamine- and maximal electroshock-induced models of amnesia in rats and showed that BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, and CbzGlnPrdN significantly prolonged conditioned passive avoidance reflex (CPAR) retention time when administered intraperitoneally (1 and 2 mg/kg) before evaluation in both models of amnesia, although CbzAlaPrdN was not effective in scopolamine-induced amnesia. Our data support previous reports on the antiamnesic effects of prolinal-based POP inhibitors and indicate an important role of POP in the regulation of learning and memory processes in the CNS.

Highlights

Proteolytic enzymes play an important role in regulating the function of endogenous peptides
We synthesized and evaluated the POPinhibitory activity of five novel KYP-2047 analogs, including BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, CbzGlnPrdN, and CbzAlaPrdN (Figure 1). Molecular modeling suggested these cyanopyrrolidine derivatives bind to POP catalytic site, and we found that CbzMetPrdN penetrates the rat blood-brain barrier (BBB) and effectively inhibits POP activity in the brain when administered intraperitoneally
Rats of groups 3–14 received a single injection of POP inhibitor at doses of 0.5, 1, and 2 mg/kg, including BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, and CbzGlnPrdN 40 min prior to the conditioned passive avoidance reflex (CPAR) learning with following maximal electroshock (MES) just after CPAR learning

Summary

INTRODUCTION

Proteolytic enzymes play an important role in regulating the function of endogenous peptides. We synthesized and evaluated the POPinhibitory activity of five novel KYP-2047 analogs, including BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, CbzGlnPrdN, and CbzAlaPrdN (Figure 1) Molecular modeling suggested these cyanopyrrolidine derivatives bind to POP catalytic site, and we found that CbzMetPrdN penetrates the rat BBB and effectively inhibits POP activity in the brain when administered intraperitoneally. Rats of groups 3–14 received a single injection of POP inhibitor at doses of 0.5, 1, and 2 mg/kg, including BocTrpPrdN (groups 3–5, n 7 in each), BocGlyPrdN (groups 6–8, n 6 in each), CbzMetPrdN (groups 9–11, n 8 in each), and CbzGlnPrdN (groups 12–14, n 8 in each) 40 min prior to the CPAR learning (three groups of animals for each inhibitor) with following MES just after CPAR learning. The predicted ability of the compounds to penetrate the blood-brain barrier (BBB) was determined in accordance with the model proposed by Suenderhauf et al (2012)

RESULTS AND DISCUSSION

DATA AVAILABILITY STATEMENT

ETHICS STATEMENT