Ultrapotent chemogenetics for research and potential clinical applications.
Animals
Chemoreceptor Cells
/ drug effects
Genetic Engineering
Haplorhini
Humans
Ligands
Mice
Mutation
Nicotinic Antagonists
/ pharmacology
Protein Domains
Receptors, Glycine
/ agonists
Receptors, Serotonin, 5-HT3
/ genetics
Smoking Cessation Agents
/ pharmacology
Tropisetron
/ pharmacology
Varenicline
/ analogs & derivatives
alpha7 Nicotinic Acetylcholine Receptor
/ agonists
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
12 04 2019
12 04 2019
Historique:
received:
30
09
2018
accepted:
15
02
2019
pubmed:
16
3
2019
medline:
10
5
2019
entrez:
16
3
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30872534
pii: science.aav5282
doi: 10.1126/science.aav5282
pmc: PMC7252514
mid: NIHMS1034353
pii:
doi:
Substances chimiques
Ligands
0
Nicotinic Antagonists
0
Receptors, Glycine
0
Receptors, Serotonin, 5-HT3
0
Smoking Cessation Agents
0
alpha7 Nicotinic Acetylcholine Receptor
0
Tropisetron
6I819NIK1W
Varenicline
W6HS99O8ZO
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : P51 OD011132
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109362
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109994
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA DA000069
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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