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Designer drugs for designer receptors: unlocking the translational potential of chemogenetics
- Source :
- Trends Pharmacol Sci, Trends in Pharmacological Sciences
- Publication Year :
- 2019
-
Abstract
- Chemogenetics enables noninvasive chemical control over cell populations in behaving animals. However, existing small-molecule agonists show insufficient potency or selectivity. There is also a need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel-based platform for cell activation and silencing that is controlled by low doses of the smoking cessation drug varenicline. We then synthesized subnanomolar-potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics.
- Subjects :
- 0301 basic medicine
Drug
alpha7 Nicotinic Acetylcholine Receptor
medicine.drug_class
media_common.quotation_subject
Tropisetron
Nicotinic Antagonists
Selective excitation
Toxicology
Ligands
Article
03 medical and health sciences
Mice
0302 clinical medicine
Receptors, Glycine
Protein Domains
medicine
Animals
Humans
Receptor
media_common
Pharmacology
Smoking Cessation Agents
Effector
Chemistry
Chemogenetics
Haplorhini
Neuromodulation (medicine)
Chemoreceptor Cells
3. Good health
Designer drug
030104 developmental biology
Mutation
Receptors, Serotonin, 5-HT3
Varenicline
Genetic Engineering
Neuroscience
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Trends Pharmacol Sci, Trends in Pharmacological Sciences
- Accession number :
- edsair.doi.dedup.....a8ade832bf56c4ca86f05c69b91ff0c0