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present the synthesis and pharmacological characterization of a series of analogs of, where the methyl group at C-3 has been replaced by different alkyl substituents.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present the synthesis and pharmacological characterization of a series of analogs of, where the methyl group at C-3 has been replaced by different alkyl substituents.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 -