Carbamoylcholine homologs: synthesis and pharmacology at nicotinic acetylcholine receptors

Anders A. Jensen; Ivan Bisgaard Mikkelsen; Bente Frølund; Karla Frydenvang; Lotte Brehm; Jerzy W Jaroszewski; Hans Bräuner-Osborne; Erik Falch; Povl Krogsgaard-Larsen

doi:10.1016/j.ejphar.2004.06.038

Carbamoylcholine homologs: synthesis and pharmacology at nicotinic acetylcholine receptors

Anders A. Jensen, Ivan Bisgaard Mikkelsen, Bente Frølund, Karla Frydenvang, Lotte Brehm, Jerzy W Jaroszewski, Hans Bräuner-Osborne, Erik Falch, Povl Krogsgaard-Larsen

8 Citations (Scopus)

Abstract

In a recent study, racemic 3-(N,N-dimethylamino)butyl-N,N-dimethylcarbamate (1) was shown to be a potent agonist at neuronal nicotinic acetylcholine receptors with a high selectivity for nicotinic over muscarinic acetylcholine receptors [Mol. Pharmacol. 64 (2003) 865-875]. Here we present the synthesis and pharmacological characterization of a series of analogs of, where the methyl group at C-3 has been replaced by different alkyl substituents. Ring systems have been incorporated into the carbon backbone of some of the molecules, or the amino group has been build into ring systems. Furthermore, the (+)- and (-)-enantiomers of have been separated, and X-ray crystallography has revealed that (-)-1 possesses (S)-configuration. The compounds have been characterized pharmacologically at recombinant nicotinic receptor subtypes. The structure-activity relationship study has provided valuable insight into the mode of interactions of and its analogs with neuronal nicotinic acetylcholine receptors.

Original language	English
Journal	European Journal of Pharmacology
Volume	497
Issue number	2
Pages (from-to)	125-37
Number of pages	13
ISSN	0014-2999
DOIs	https://doi.org/10.1016/j.ejphar.2004.06.038
Publication status	Published - 2004

Keywords

Animals
Carbachol
Cell Line
Dose-Response Relationship, Drug
Humans
Protein Binding
Rats
Receptors, Nicotinic
Structure-Activity Relationship

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10.1016/j.ejphar.2004.06.038

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@article{bbb732914b7540ef9cae285d4ee7aa0c,

title = "Carbamoylcholine homologs: synthesis and pharmacology at nicotinic acetylcholine receptors",

abstract = "In a recent study, racemic 3-(N,N-dimethylamino)butyl-N,N-dimethylcarbamate (1) was shown to be a potent agonist at neuronal nicotinic acetylcholine receptors with a high selectivity for nicotinic over muscarinic acetylcholine receptors [Mol. Pharmacol. 64 (2003) 865-875]. Here we present the synthesis and pharmacological characterization of a series of analogs of, where the methyl group at C-3 has been replaced by different alkyl substituents. Ring systems have been incorporated into the carbon backbone of some of the molecules, or the amino group has been build into ring systems. Furthermore, the (+)- and (-)-enantiomers of have been separated, and X-ray crystallography has revealed that (-)-1 possesses (S)-configuration. The compounds have been characterized pharmacologically at recombinant nicotinic receptor subtypes. The structure-activity relationship study has provided valuable insight into the mode of interactions of and its analogs with neuronal nicotinic acetylcholine receptors.",

keywords = "Animals, Carbachol, Cell Line, Dose-Response Relationship, Drug, Humans, Protein Binding, Rats, Receptors, Nicotinic, Structure-Activity Relationship",

author = "Jensen, {Anders A.} and Mikkelsen, {Ivan Bisgaard} and Bente Fr{\o}lund and Karla Frydenvang and Lotte Brehm and Jaroszewski, {Jerzy W} and Hans Br{\"a}uner-Osborne and Erik Falch and Povl Krogsgaard-Larsen",

year = "2004",

doi = "10.1016/j.ejphar.2004.06.038",

language = "English",

volume = "497",

pages = "125--37",

journal = "European Journal of Pharmacology",

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TY - JOUR

T1 - Carbamoylcholine homologs

T2 - synthesis and pharmacology at nicotinic acetylcholine receptors

AU - Jensen, Anders A.

AU - Mikkelsen, Ivan Bisgaard

AU - Frølund, Bente

AU - Frydenvang, Karla

AU - Brehm, Lotte

AU - Jaroszewski, Jerzy W

AU - Bräuner-Osborne, Hans

AU - Falch, Erik

AU - Krogsgaard-Larsen, Povl

PY - 2004

Y1 - 2004

N2 - In a recent study, racemic 3-(N,N-dimethylamino)butyl-N,N-dimethylcarbamate (1) was shown to be a potent agonist at neuronal nicotinic acetylcholine receptors with a high selectivity for nicotinic over muscarinic acetylcholine receptors [Mol. Pharmacol. 64 (2003) 865-875]. Here we present the synthesis and pharmacological characterization of a series of analogs of, where the methyl group at C-3 has been replaced by different alkyl substituents. Ring systems have been incorporated into the carbon backbone of some of the molecules, or the amino group has been build into ring systems. Furthermore, the (+)- and (-)-enantiomers of have been separated, and X-ray crystallography has revealed that (-)-1 possesses (S)-configuration. The compounds have been characterized pharmacologically at recombinant nicotinic receptor subtypes. The structure-activity relationship study has provided valuable insight into the mode of interactions of and its analogs with neuronal nicotinic acetylcholine receptors.

AB - In a recent study, racemic 3-(N,N-dimethylamino)butyl-N,N-dimethylcarbamate (1) was shown to be a potent agonist at neuronal nicotinic acetylcholine receptors with a high selectivity for nicotinic over muscarinic acetylcholine receptors [Mol. Pharmacol. 64 (2003) 865-875]. Here we present the synthesis and pharmacological characterization of a series of analogs of, where the methyl group at C-3 has been replaced by different alkyl substituents. Ring systems have been incorporated into the carbon backbone of some of the molecules, or the amino group has been build into ring systems. Furthermore, the (+)- and (-)-enantiomers of have been separated, and X-ray crystallography has revealed that (-)-1 possesses (S)-configuration. The compounds have been characterized pharmacologically at recombinant nicotinic receptor subtypes. The structure-activity relationship study has provided valuable insight into the mode of interactions of and its analogs with neuronal nicotinic acetylcholine receptors.

KW - Animals

KW - Carbachol

KW - Cell Line

KW - Dose-Response Relationship, Drug

KW - Humans

KW - Protein Binding

KW - Rats

KW - Receptors, Nicotinic

KW - Structure-Activity Relationship

U2 - 10.1016/j.ejphar.2004.06.038

DO - 10.1016/j.ejphar.2004.06.038

M3 - Journal article

C2 - 15306197

SN - 0014-2999

VL - 497

SP - 125

EP - 137

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 2

ER -

Carbamoylcholine homologs: synthesis and pharmacology at nicotinic acetylcholine receptors

Abstract

Keywords

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