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 -