Abstract
A duplexed, functional multiaddition high throughput screen and subsequent iterative parallel synthesis effort identified the first highly selective and CNS penetrant glucagon-like peptide-1R (GLP-1R) positive allosteric modulator (PAM). PAM (S)-9b potentiated low-dose exenatide to augment insulin secretion in primary mouse pancreatic islets, and (S)-9b alone was effective in potentiating endogenous GLP-1R to reverse haloperidol-induced catalepsy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation / drug effects
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Animals
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Catalepsy / chemically induced
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Catalepsy / drug therapy
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Central Nervous System Agents / therapeutic use
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Drug Synergism
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Exenatide
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Glucagon-Like Peptide 1 / pharmacology
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Glucagon-Like Peptide-1 Receptor
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Haloperidol
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High-Throughput Screening Assays
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Indoles / chemical synthesis*
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Indoles / metabolism
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Insulin / metabolism
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Insulin Secretion
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Islets of Langerhans / drug effects
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Male
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Mice, Inbred C57BL
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Microsomes, Liver / metabolism
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Peptides / pharmacology
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / metabolism
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology
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Receptors, Glucagon / drug effects*
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Structure-Activity Relationship
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Venoms / pharmacology
Substances
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(S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido(3,4-b)indole-4-carboxamide
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Central Nervous System Agents
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Glp1r protein, mouse
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Glucagon-Like Peptide-1 Receptor
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Indoles
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Insulin
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Peptides
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Pyrrolidines
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Receptors, Glucagon
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Venoms
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Glucagon-Like Peptide 1
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Exenatide
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Haloperidol