title: Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM).
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.
authors.affiliation: Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, ‡Department of Pharmacology, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States .
authors.forename: Lindsey C
authors.initials: LC
authors.lastname: Morris
authors.forename: Kellie D
authors.initials: KD
authors.lastname: Nance
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Gentry
authors.forename: Emily L
authors.initials: EL
authors.lastname: Days
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Analisa D
authors.initials: AD
authors.lastname: Thompson
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Chuck W
authors.initials: CW
authors.lastname: Locuson
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morrison
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Niswender
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D002491:Central Nervous System Agents / Q000627:therapeutic use; D004357:Drug Synergism; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006220:Haloperidol; D057166:High-Throughput Screening Assays; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014688:Venoms / Q000494:pharmacology
chemical_list: C000595471:(S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido(3,4-b)indole-4-carboxamide; D002491:Central Nervous System Agents; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007211:Indoles; D007328:Insulin; D010455:Peptides; D011759:Pyrrolidines; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D006220:Haloperidol