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Molecular Pharmacology

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Research ArticleArticle

Carbamoylcholine Homologs: Novel and Potent Agonists at Neuronal Nicotinic Acetylcholine Receptors

Anders A. Jensen, Ivan Mikkelsen, Bente Frølund, Hans Bräuner-Osborne, Erik Falch and Povl Krogsgaard-Larsen
Molecular Pharmacology October 2003, 64 (4) 865-875; DOI: https://doi.org/10.1124/mol.64.4.865
Anders A. Jensen
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Ivan Mikkelsen
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Bente Frølund
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Hans Bräuner-Osborne
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Erik Falch
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Povl Krogsgaard-Larsen
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Abstract

The classic muscarinic acetylcholine receptor (mAChR) agonist carbamoylcholine (carbachol) does not seem to be the most obvious lead for the development of selective ligands at nicotinic acetylcholine receptors (nAChRs). In the past, however, N-methylations of carbachol have provided N-methylcarbamoylcholine and N,N-dimethylcarbamoylcholine (DMCC), which predominantly display nicotinic activity. In this study, 12 homologous analogs of DMCC and its corresponding tertiary amine, N,N-dimethylcarbamoyl-N,N-dimethylaminoethanol, were synthesized and their binding affinities to native mAChR and nAChR sites estimated. One of the compounds in the series, 3-N,N-dimethylaminobutyl-N,N-dimethylcarbamate (7), displayed low nanomolar binding affinity to nAChRs and a 400-fold selectivity for nAChRs over mAChRs. Hence, a new series of compounds was synthesized in which alkyl and aryl groups and different ring systems were introduced in the carbamate moiety of 7. In a [3H]epibatidine binding assay, the Ki values of 7 and its analogs at rat α2β2, α4β2, α2β4, α3β4, and α4β4 nAChRs, stably expressed in mammalian cell lines, ranged from low nanomolar to midmicromolar concentrations, whereas all of the compounds displayed weak binding to an α7/5-HT3 chimera and to native mAChRs. Compound 7 and its analogs were determined to be agonists at the α3β4 nAChR subtype. This series includes the most potent and selective nicotinic agonists structurally derived from ACh to date. Furthermore, the compounds are tertiary amines, implying some advantages in terms of bioavailability pertinent to future in vivo pharmacological studies. Finally, observations made in the study hold promising perspectives for future development of ligands selective for specific nAChR subtypes.

  • Received April 29, 2003.
  • Accepted June 30, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 64 (4)
Molecular Pharmacology
Vol. 64, Issue 4
1 Oct 2003
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Research ArticleArticle

Carbamoylcholine Homologs: Novel and Potent Agonists at Neuronal Nicotinic Acetylcholine Receptors

Anders A. Jensen, Ivan Mikkelsen, Bente Frølund, Hans Bräuner-Osborne, Erik Falch and Povl Krogsgaard-Larsen
Molecular Pharmacology October 1, 2003, 64 (4) 865-875; DOI: https://doi.org/10.1124/mol.64.4.865

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Research ArticleArticle

Carbamoylcholine Homologs: Novel and Potent Agonists at Neuronal Nicotinic Acetylcholine Receptors

Anders A. Jensen, Ivan Mikkelsen, Bente Frølund, Hans Bräuner-Osborne, Erik Falch and Povl Krogsgaard-Larsen
Molecular Pharmacology October 1, 2003, 64 (4) 865-875; DOI: https://doi.org/10.1124/mol.64.4.865
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