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Bioorg Med Chem Lett. 2016 Dec 1;26(23):5613-5617. doi: 10.1016/j.bmcl.2016.10.078. Epub 2016 Oct 27.

Novel 5-substituted 3-hydroxyphenyl and 3-nitrophenyl ethers of S-prolinol as α4β2-nicotinic acetylcholine receptor ligands.

Author information

1
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
2
CNR, Istituto di Neuroscienze, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, via Vanvitelli 32, I-20129 Milano, Italy.
3
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via Mangiagalli 25, I-20133 Milano, Italy. Electronic address: marco.pallavicini@unimi.it.

Abstract

A series of 3-nitrophenyl and 3-hydroxyphenyl ethers of (S)-N-methylprolinol bearing bulky and lipophilic substituents at phenyl C5 were tested for affinity at α4β2 and α3β4 nAChRs. The two phenyl ethers 5-substituted with 6-hydroxy-1-hexynyl showed high α4β2 affinity and significantly increased α4β2/α3β4 selectivity compared to the respective unsubstituted parent compounds. Within the two series of novel phenyl ethers, we observed parallel shifts in affinity and, furthermore, the increase in α4β2/α3β4 selectivity resulting from the hydroxyalkynyl substitution parallels that reported for the same modification at the 3-pyridyl ether of (S)-N-methylprolinol (A-84543), a well-known potent α4β2 agonist. On the basis of these results, our nitrophenyl and hydroxyphenyl prolinol ethers can be considered bioisosteres of the pyridyl ether A-84543 and lead compounds candidable to analogous optimization processes.

KEYWORDS:

6-Hydroxy-1-hexinyl; A-84543; Affinity; Bioisosterism; Ligand; nAChR

PMID:
27818109
DOI:
10.1016/j.bmcl.2016.10.078
[Indexed for MEDLINE]

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