TY - JOUR

T1 - In Vitro and In Vivo Evaluation of Pellotine

T2 - A Hypnotic Lophophora Alkaloid

AU - Poulie, Christian B M

AU - Chan, Camilla B

AU - Parka, Aleksandra

AU - Lettorp, Magnus

AU - Vos, Josephine

AU - Raaschou, Amanda

AU - Pottie, Eline

AU - Bundgaard, Mikkel S

AU - Sørensen, Louis M E

AU - Cecchi, Claudia R

AU - Märcher-Rørsted, Emil

AU - Bach, Anders

AU - Herth, Matthias M

AU - Decker, Ann

AU - Jensen, Anders A

AU - Elfving, Betina

AU - Kretschmann, Andreas C

AU - Stove, Christophe P

AU - Kohlmeier, Kristi A

AU - Cornett, Claus

AU - Janfelt, Christian

AU - Kornum, Birgitte R

AU - Kristensen, Jesper L

N1 - © 2023 American Chemical Society.

PY - 2023

Y1 - 2023

N2 - Quality of life is often reduced in patients with sleep-wake disorders. Insomnia is commonly treated with benzodiazepines, despite their well-known side effects. Pellotine (1), a Lophophora alkaloid, has been reported to have short-acting sleep-inducing properties in humans. In this study, we set out to evaluate various in vitro and in vivo properties of 1. We demonstrate that 1 undergoes slow metabolism; e.g. in mouse liver microsomes 65% remained, and in human liver microsomes virtually no metabolism was observed after 4 h. In mouse liver microsomes, two phase I metabolites were identified: 7-desmethylpellotine and pellotine-N-oxide. In mice, the two diastereomers of pellotine-O-glucuronide were additionally identified as phase II metabolites. Furthermore, we demonstrated by DESI-MSI that 1 readily enters the central nervous system of rodents. Furthermore, radioligand-displacement assays showed that 1 is selective for the serotonergic system and in particular the serotonin (5-HT)1D, 5-HT6, and 5-HT7 receptors, where it binds with affinities in the nanomolar range (117, 170, and 394 nM, respectively). Additionally, 1 was functionally characterized at 5-HT6 and 5-HT7, where it was found to be an agonist at the former (EC50 = 94 nM, Emax = 32%) and an inverse agonist at the latter (EC50 = 291 nM, Emax = -98.6). Finally, we demonstrated that 1 dose-dependently decreases locomotion in mice, inhibits REM sleep, and promotes sleep fragmentation. Thus, we suggest that pellotine itself, and not an active metabolite, is responsible for the hypnotic effects and that these effects are possibly mediated through modulation of serotonergic receptors.

AB - Quality of life is often reduced in patients with sleep-wake disorders. Insomnia is commonly treated with benzodiazepines, despite their well-known side effects. Pellotine (1), a Lophophora alkaloid, has been reported to have short-acting sleep-inducing properties in humans. In this study, we set out to evaluate various in vitro and in vivo properties of 1. We demonstrate that 1 undergoes slow metabolism; e.g. in mouse liver microsomes 65% remained, and in human liver microsomes virtually no metabolism was observed after 4 h. In mouse liver microsomes, two phase I metabolites were identified: 7-desmethylpellotine and pellotine-N-oxide. In mice, the two diastereomers of pellotine-O-glucuronide were additionally identified as phase II metabolites. Furthermore, we demonstrated by DESI-MSI that 1 readily enters the central nervous system of rodents. Furthermore, radioligand-displacement assays showed that 1 is selective for the serotonergic system and in particular the serotonin (5-HT)1D, 5-HT6, and 5-HT7 receptors, where it binds with affinities in the nanomolar range (117, 170, and 394 nM, respectively). Additionally, 1 was functionally characterized at 5-HT6 and 5-HT7, where it was found to be an agonist at the former (EC50 = 94 nM, Emax = 32%) and an inverse agonist at the latter (EC50 = 291 nM, Emax = -98.6). Finally, we demonstrated that 1 dose-dependently decreases locomotion in mice, inhibits REM sleep, and promotes sleep fragmentation. Thus, we suggest that pellotine itself, and not an active metabolite, is responsible for the hypnotic effects and that these effects are possibly mediated through modulation of serotonergic receptors.

U2 - 10.1021/acsptsci.3c00142

DO - 10.1021/acsptsci.3c00142

M3 - Journal article

C2 - 37854625

VL - 6

SP - 1492

EP - 1507

JO - ACS Pharmacology and Translational Science

JF - ACS Pharmacology and Translational Science

SN - 2575-9108

IS - 10

ER -