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Characterization of Ultrapotent Chemogenetic Ligands for Research Applications in Nonhuman Primates

Lookup NU author(s): Dr Mark EldridgeORCiD

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Abstract

© 2022 American Chemical Society. Chemogenetics is a technique for obtaining selective pharmacological control over a cell population by expressing an engineered receptor that is selectively activated by an exogenously administered ligand. A promising approach for neuronal modulation involves the use of "Pharmacologically Selective Actuator Modules"(PSAMs); these chemogenetic receptors are selectively activated by ultrapotent "Pharmacologically Selective Effector Molecules"(uPSEMs). To extend the use of PSAM/PSEMs to studies in nonhuman primates, it is necessary to thoroughly characterize the efficacy and safety of these tools. We describe the time course and brain penetrance in rhesus monkeys of two compounds with promising binding specificity and efficacy profiles in in vitro studies, uPSEM792 and uPSEM817, after systemic administration. Rhesus monkeys received subcutaneous (s.c.) or intravenous (i.v.) administration of uPSEM817 (0.064 mg/kg) or uPSEM792 (0.87 mg/kg), and plasma and cerebrospinal fluid samples were collected over 48 h. Both compounds exhibited good brain penetrance, relatively slow washout, and negligible conversion to potential metabolites varenicline or hydroxyvarenicline. In addition, we found that neither of these uPSEMs significantly altered the heart rate or sleep. Our results indicate that both compounds are suitable candidates for neuroscience studies using PSAMs in nonhuman primates.

Publication metadata

Author(s): Raper J, Eldridge MAG, Sternson SM, Shim JY, Fomani GP, Richmond BJ, Wichmann T, Galvan A

Publication type: Article

Publication status: Published

Journal: ACS Chemical Neuroscience

Year: 2022

Volume: 13

Issue: 21

Pages: 3118-3125

Print publication date: 02/11/2022

Online publication date: 24/10/2022

Acceptance date: 12/10/2022

ISSN (electronic): 1948-7193

Publisher: American Chemical Society

URL: https://doi.org/10.1021/acschemneuro.2c00525

DOI: 10.1021/acschemneuro.2c00525

PubMed id: 36279419

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