Conformationally restrained carbamoylcholine homologues. Synthesis, pharmacology at neuronal nicotinic acetylcholine receptors and biostructural considerations

M de la Fuente Revenga; Thomas Balle; Anders A. Jensen; Bente Frølund

doi:10.1016/j.ejmech.2015.07.029

Conformationally restrained carbamoylcholine homologues. Synthesis, pharmacology at neuronal nicotinic acetylcholine receptors and biostructural considerations

M de la Fuente Revenga, Thomas Balle, Anders A. Jensen, Bente Frølund

4 Citations (Scopus)

Abstract

Exploration of small selective ligands for the nicotinic acetylcholine receptors (nAChRs) based on acetylcholine (ACh) has led to the development of potent agonists with clear preference for the α4β2 nAChR, the most prevalent nAChR subtype in the central nervous system. In this work we present the continuation of these efforts aimed at increasing this subtype selectivity by introduction of conformational restriction in the carbamoylcholine homologue, 3-(dimethylaminobutyl) dimethylcarbamate (DMABC). Our results highlight the importance of the N-carbamoyl substitution in α4β2-subtype selectivity. Moreover, we have confirmed the non-linear conformation of DMABC bound to nAChRs suggested by recent crystal structures of the compound in complex with the Lymnaea stagnalis ACh binding protein.

Original language	English
Journal	European Journal of Medicinal Chemistry
Volume	102
Pages (from-to)	352-362
Number of pages	11
ISSN	0223-5234
DOIs	https://doi.org/10.1016/j.ejmech.2015.07.029
Publication status	Published - 16 Jul 2015

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Conformationally restrained carbamoylcholine homologues. Synthesis, pharmacology at neuronal nicotinic acetylcholine receptors and biostructural considerations. / de la Fuente Revenga, M; Balle, Thomas; Jensen, Anders A. et al.
In: European Journal of Medicinal Chemistry, Vol. 102, 16.07.2015, p. 352-362 .

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AU - de la Fuente Revenga, M

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AU - Jensen, Anders A.

AU - Frølund, Bente

PY - 2015/7/16

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N2 - Exploration of small selective ligands for the nicotinic acetylcholine receptors (nAChRs) based on acetylcholine (ACh) has led to the development of potent agonists with clear preference for the α4β2 nAChR, the most prevalent nAChR subtype in the central nervous system. In this work we present the continuation of these efforts aimed at increasing this subtype selectivity by introduction of conformational restriction in the carbamoylcholine homologue, 3-(dimethylaminobutyl) dimethylcarbamate (DMABC). Our results highlight the importance of the N-carbamoyl substitution in α4β2-subtype selectivity. Moreover, we have confirmed the non-linear conformation of DMABC bound to nAChRs suggested by recent crystal structures of the compound in complex with the Lymnaea stagnalis ACh binding protein.

AB - Exploration of small selective ligands for the nicotinic acetylcholine receptors (nAChRs) based on acetylcholine (ACh) has led to the development of potent agonists with clear preference for the α4β2 nAChR, the most prevalent nAChR subtype in the central nervous system. In this work we present the continuation of these efforts aimed at increasing this subtype selectivity by introduction of conformational restriction in the carbamoylcholine homologue, 3-(dimethylaminobutyl) dimethylcarbamate (DMABC). Our results highlight the importance of the N-carbamoyl substitution in α4β2-subtype selectivity. Moreover, we have confirmed the non-linear conformation of DMABC bound to nAChRs suggested by recent crystal structures of the compound in complex with the Lymnaea stagnalis ACh binding protein.

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Conformationally restrained carbamoylcholine homologues. Synthesis, pharmacology at neuronal nicotinic acetylcholine receptors and biostructural considerations

Abstract

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