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Bridging Interventional Development Gaps

Large-Scale Synthesis of Clozapine-N-Oxide

G protein–coupled receptor (GPCR) signaling pathways are involved in many diseases, including diabetes, some forms of blindness, allergies, depression, heart problems and some cancers. GPCRs are proteins that help to control cells by carrying messages from outside the cell to its interior, altering the cell’s state. Many modern drugs target GPCRs; a well-known example is Zantac. In an effort to better understand GPCR action and to learn to control it, scientists have developed tools called “receptors activated solely by synthetic ligands” (RASSLs), meaning that the GPCR itself has been modified so it no longer responds to natural cues, but is instead activated only by an engineered molecule that has no natural role in the body. The researchers are working to manufacture a particular engineered GPCR-activating molecule called clozapine-N-oxide (CNO) in large enough quantities to substantially reduce its cost so that it can be more widely available for researchers using RASSLs.

Scientific Synopsis

RASSLs (receptors activated solely by synthetic ligands) are based on the observation that GPCRs, the largest and most diverse family of cell-surface signaling molecules in the human genome (e.g., dopamine receptors), can be altered to eliminate response to the native ligand while retaining, inducing or enhancing agonist activity of a small molecule. The most recent development in this technology has been the development of RASSLs based on muscarinic receptor subtypes that respond to clozapine-N-oxide (CNO). Because CNO is otherwise pharmacologically inert, it has the capacity to pair with the appropriate RASSL to enable a novel type of pharmacology that depends on localized expression of an engineered drug receptor in a specific tissue. The common goal of the RASSL study group is to make important reagents available to investigators focused on the potential use of RASSLs to treat disease. Members of the group have been generous in making cDNAs and vectors encoding RASSLs available to other investigators.

The immediate goal of this proposal is to make a very expensive ligand (CNO) more broadly available in order to accelerate translational studies in areas supported by a number of Institutes (NINDS, NIDCR, NHLBI, NCI and NIMH). Accordingly, we request from the program that approximately 100 gm of CNO be synthesized at >98 percent purity in 100 × 1 gm aliquots and that this material be made available to qualified investigators. Currently, CNO is commercially available from Biomol, Inc., for about $7,000 per gm. Economies of scale should be able to reduce the cost greatly and be of direct benefit both to the NIH’s intramural investigators and to its extramural investigators, thereby resulting in more efficient use of public research funds. This material support is in turn likely to foster broader translational use of RASSLs.

Lead Collaborators

University of California, San Francisco
John Forsayeth, Ph.D.
, Bruce Conklin, M.D.

National Institute of Dental and Craniofacial Research, NIH
J. Silvio Gutkind, Ph.D.

National Institute of Diabetes and Digestive and Kidney Diseases, NIH
Jurgen Wess, Ph.D.

University of North Carolina at Chapel Hill
Bryan Roth, M.D., Ph.D.

Public Health Impact

The immediate goal of this proposal is to make a very expensive ligand (clozapine-N-oxide) more broadly available in order to accelerate translational studies in areas supported by a number of NIH Institutes (NINDS, NIDCR, NHLBI, NCI and NIMH).

Outcomes

Work on this project is complete.

Project Details

  • Synthesis of Good Manufacturing Practice (GMP) material
Last updated: 07-25-2017
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