Carbamoylcholine Homologs: Novel and Potent Agonists at Neuronal Nicotinic Acetylcholine Receptors
| Autor: | Povl Krogsgaard-Larsen, Bente Frølund, Erik Falch, Anders A. Jensen, Ivan Mikkelsen, Hans Bräuner-Osborne |
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| Rok vydání: | 2003 |
| Předmět: |
Agonist
Nicotine Carbachol Tertiary amine Pyridines medicine.drug_class Stereochemistry Aconitine Nicotinic Antagonists Receptors Nicotinic Tritium Binding Competitive Ganglion type nicotinic receptor Muscarinic acetylcholine receptor medicine Animals Humans Nicotinic Agonists Cells Cultured Acetylcholine receptor Pharmacology Chemistry Parasympatholytics N-Methylscopolamine Bridged Bicyclo Compounds Heterocyclic Rats Nicotinic agonist Biochemistry Receptors Serotonin Epibatidine Molecular Medicine Receptors Serotonin 5-HT3 medicine.drug |
| Zdroj: | Molecular Pharmacology. 64:865-875 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.64.4.865 |
| Popis: | 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 alpha2beta2, alpha4beta2, alpha2beta4, alpha3beta4, and alpha4beta4 nAChRs, stably expressed in mammalian cell lines, ranged from low nanomolar to midmicromolar concentrations, whereas all of the compounds displayed weak binding to an alpha7/5-HT3 chimera and to native mAChRs. Compound 7 and its analogs were determined to be agonists at the alpha3beta4 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. |
| Databáze: | OpenAIRE |
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