Abstract
Löffler et al . highlight the important potential of designer receptors exclusively activated by a designer drug (DREADD)–based technologies to study cell type–specific functions but cautions that the triggering DREADD ligand, clozapine- N -oxide (CNO) might, through potential conversion products, have bioactivity outside of the synthetic DREADD receptor system and maintains that Ray et al . did not control for such activity. We recount controls used in our work that indicated no discernible DREADD-independent effects of CNO on the homeostatic assays employed and discuss in this regard murine studies reporting CNO bioneutrality in other assays, the rapid renal clearance of N-oxides like CNO, and evidence of negligible conversion to clozapine (CN) in mice and rats.
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