title: Beta and gamma carboline derivatives as potential anti-Alzheimer agents: A comparison.
abstract: Nine novel β- and γ-carboline derivatives bearing either methyl-, propargyl- or phenethyl-residues at the indole nitrogen were synthesized and tested as potential anti-Alzheimer drugs. Antagonism of recombinantly expressed NMDA receptors, inhibition of cholinesterases, and radical scavenging properties were determined for all compounds. Some were additionally tested in vivo for their ability to reverse scopolamine-induced cognitive impairment in an 8-arm radial maze experiment with rats. For the most promising candidates, the interaction with muscarinic M1 receptors was also investigated. With this set of compounds assays the influence of the scaffold itself and the substituents can be investigated separately. 5-Methyl-γ-carboline (6) was the most potent (0.25 μmol/100 g b.w.) compound in the in vivo test and might be a good starting point for the development of novel anti-Alzheimer drugs.
authors.affiliation: Pharmaceutical / Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: robert.otto@uni-jena.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Otto
authors.affiliation: Pharmaceutical Biology, Institute of Pharmacy, Friedrich-Schiller-University, Semmelweisstr. 10, D-07743 Jena, Germany. Electronic address: robert.penzis@uni-jena.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Penzis
authors.affiliation: Pharmaceutical Biology, Institute of Pharmacy, Friedrich-Schiller-University, Semmelweisstr. 10, D-07743 Jena, Germany. Electronic address: Friedemann.gaube@uni-jena.de.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Gaube
authors.affiliation: Pharmaceutical Biology, Institute of Pharmacy, Friedrich-Schiller-University, Semmelweisstr. 10, D-07743 Jena, Germany. Electronic address: t.winckler@uni-jena.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Winckler
authors.affiliation: Institute for Pharmacology and Toxicology, Friedrich-Schiller-University, Drackendorfer Str. 1, D-07747 Jena, Germany. Electronic address: dorothea.appenroth@mti.uni-jena.de.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Appenroth
authors.affiliation: Institute for Pharmacology and Toxicology, Friedrich-Schiller-University, Drackendorfer Str. 1, D-07747 Jena, Germany. Electronic address: christian.fleck@mti.uni-jena.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Fleck
authors.affiliation: Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-University, Gerhard-Domagk-Str.3, D-53121 Bonn, Germany. Electronic address: traenkle@uni-bonn.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Tränkle
authors.affiliation: Pharmaceutical / Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
authors.affiliation: Institute for Organic and Macromolecular Chemistry, Friedrich-Schiller-University, Humboldtstr. 10, D-07743 Jena, Germany. Electronic address: ch.enzensperger@uni-jena.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Enzensperger
mesh_terms: D000759:Adjuvants, Anesthesia / Q000633:toxicity; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology*; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D005260:Female; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012601:Scopolamine / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000759:Adjuvants, Anesthesia; D014151:Anti-Anxiety Agents; D002243:Carbolines; D016194:Receptors, N-Methyl-D-Aspartate; C055572:gamma-carboline; D012601:Scopolamine
keywords: Alzheimer's disease; Carboline; Neurological agents; Neuroprotective; Structure-activity relationships