Design, synthesis and biological evaluation of Erythrina alkaloid analogues as neuronal nicotinic acetylcholine receptor antagonists

François Crestey; Anders A. Jensen; Morten Borch; Jesper Andreasen T.; Jacob Andersen; Thomas Balle; Jesper Langgaard Kristensen

doi:10.1021/jm4013592

Design, synthesis and biological evaluation of Erythrina alkaloid analogues as neuronal nicotinic acetylcholine receptor antagonists

François Crestey, Anders A. Jensen, Morten Borch, Jesper Andreasen T., Jacob Andersen, Thomas Balle, Jesper Langgaard Kristensen

Department of Drug Design and Pharmacology

34 Citations (Scopus)

Abstract

The synthesis of a new series of Erythrina alkaloid analogues and their pharmacological characterization at various nicotine acetylcholine receptor (nAChR) subtypes are described. The compounds were designed to be simplified analogues of aromatic erythrinanes with the aim of obtaining subtype-selective antagonists for the nAChRs and thereby probe the potential of using these natural products as scaffolds for further ligand optimization. The most selective and potent nAChR ligand to come from the series, 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (3c) (also a natural product by the name of O-methylcorypalline), displayed submicromolar binding affinity toward the α4β2 nAChR with more than 300-fold selectivity over α4β4, α3β4, and α7. Furthermore, this lead structure (which also has inhibitory activity at monoamine oxidases A and B and at the serotonin and norepinephrine transporters) showed antidepressant-like effect in the mouse forced swim test at 30 mg/kg.

Original language	Danish
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	23
Pages (from-to)	9673-9682
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm4013592
Publication status	Published - 12 Dec 2013

Access to Document

10.1021/jm4013592

Cite this

@article{4724187472e640928d36d154d97f750c,

title = "Design, synthesis and biological evaluation of Erythrina alkaloid analogues as neuronal nicotinic acetylcholine receptor antagonists",

abstract = "The synthesis of a new series of Erythrina alkaloid analogues and their pharmacological characterization at various nicotine acetylcholine receptor (nAChR) subtypes are described. The compounds were designed to be simplified analogues of aromatic erythrinanes with the aim of obtaining subtype-selective antagonists for the nAChRs and thereby probe the potential of using these natural products as scaffolds for further ligand optimization. The most selective and potent nAChR ligand to come from the series, 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (3c) (also a natural product by the name of O-methylcorypalline), displayed submicromolar binding affinity toward the α4β2 nAChR with more than 300-fold selectivity over α4β4, α3β4, and α7. Furthermore, this lead structure (which also has inhibitory activity at monoamine oxidases A and B and at the serotonin and norepinephrine transporters) showed antidepressant-like effect in the mouse forced swim test at 30 mg/kg.",

author = "Fran{\c c}ois Crestey and Jensen, {Anders A.} and Morten Borch and {Andreasen T.}, Jesper and Jacob Andersen and Thomas Balle and Kristensen, {Jesper Langgaard}",

year = "2013",

month = dec,

day = "12",

doi = "10.1021/jm4013592",

language = "Dansk",

volume = "56",

pages = "9673--9682",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "23",

}

TY - JOUR

T1 - Design, synthesis and biological evaluation of Erythrina alkaloid analogues as neuronal nicotinic acetylcholine receptor antagonists

AU - Crestey, François

AU - Jensen, Anders A.

AU - Borch, Morten

AU - Andreasen T., Jesper

AU - Andersen, Jacob

AU - Balle, Thomas

AU - Kristensen, Jesper Langgaard

PY - 2013/12/12

Y1 - 2013/12/12

N2 - The synthesis of a new series of Erythrina alkaloid analogues and their pharmacological characterization at various nicotine acetylcholine receptor (nAChR) subtypes are described. The compounds were designed to be simplified analogues of aromatic erythrinanes with the aim of obtaining subtype-selective antagonists for the nAChRs and thereby probe the potential of using these natural products as scaffolds for further ligand optimization. The most selective and potent nAChR ligand to come from the series, 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (3c) (also a natural product by the name of O-methylcorypalline), displayed submicromolar binding affinity toward the α4β2 nAChR with more than 300-fold selectivity over α4β4, α3β4, and α7. Furthermore, this lead structure (which also has inhibitory activity at monoamine oxidases A and B and at the serotonin and norepinephrine transporters) showed antidepressant-like effect in the mouse forced swim test at 30 mg/kg.

AB - The synthesis of a new series of Erythrina alkaloid analogues and their pharmacological characterization at various nicotine acetylcholine receptor (nAChR) subtypes are described. The compounds were designed to be simplified analogues of aromatic erythrinanes with the aim of obtaining subtype-selective antagonists for the nAChRs and thereby probe the potential of using these natural products as scaffolds for further ligand optimization. The most selective and potent nAChR ligand to come from the series, 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (3c) (also a natural product by the name of O-methylcorypalline), displayed submicromolar binding affinity toward the α4β2 nAChR with more than 300-fold selectivity over α4β4, α3β4, and α7. Furthermore, this lead structure (which also has inhibitory activity at monoamine oxidases A and B and at the serotonin and norepinephrine transporters) showed antidepressant-like effect in the mouse forced swim test at 30 mg/kg.

U2 - 10.1021/jm4013592

DO - 10.1021/jm4013592

M3 - Tidsskriftartikel

C2 - 24187998

SN - 0022-2623

VL - 56

SP - 9673

EP - 9682

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 23

ER -