Characterization of Ultrapotent Chemogenetic Ligands for Research Applications in Nonhuman Primates

ACS Chem Neurosci. 2022 Nov 2;13(21):3118-3125. doi: 10.1021/acschemneuro.2c00525. Epub 2022 Oct 24.

Abstract

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.

Keywords: chemogenetics; ligand-gated ion channels; pharmacokinetics; rhesus macaque; uPSEMs; varenicline.

MeSH terms

  • Animals
  • Brain* / physiology
  • Ligands
  • Macaca mulatta
  • Neurons* / physiology
  • Varenicline

Substances

  • Ligands
  • Varenicline