Chemogenetics revealed: converted clozapine activates lab-designed neuronal receptors

2017

Challenge

Designer Receptors Exclusively Activated by Designer Drugs (DREADD) is a chemogenetic technology used in hundreds of laboratories around the world to modulate neuronal activity in freely-moving animals. It has also been applied to nonhuman primates and is considered amenable for translation to humans as a next-generation therapeutic strategy for the control of discrete brain cell populations underlying neurological disorders. However, the chemical that was initially developed to bind and activate such lab-designed receptors, clozapine N-oxide (CNO), was never properly characterized and cannot be used in humans.

Advance

IRP researchers led by Michael Michaelides, Ph.D., discovered that DREADDs are activated in vivo not by the CNO molecule itself but rather by clozapine, a compound formed inside the body by converting CNO. Clozapine is a commonly used FDA-approved antipsychotic medication. Clozapine preferentially and potently activates DREADD receptors at doses lower than those typically administered to human patients.

Impact

With this new understanding, and because clozapine has been administered to humans for decades and has a well-known safety profile, it can be used in future attempts to translate the DREADD neuromodulation technology for therapeutic purposes in humans. The team’s discovery that clozapine potently activates DREADD receptors in vivo has spurred Dr. Michaelides and his team to develop novel chemogenetic compounds based on clozapine’s structure that may have theranostic — that is, both diagnostic (via PET imaging) and therapeutic — potential.

Publications

Gomez JL, Bonaventura J, Lesniak W, Mathews WB, Sysa Shah P, Rodriguez LA, Ellis RJ, Ritchie C, Harvey B, Dannals RF, Pomper MG, Bonci A, Michaelides M. (2017). Chemogenetics revealed –DREADD occupancy and activation via converted clozapine. Science. Aug 4;357(6350):503-507.