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

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 alpha 4 beta 2 and alpha 3 beta 4 nAChRs. The two phenyl ethers 5-substituted with 6-hydroxy-1-hexynyl showed high a4b2 affinity and significantly increased alpha 4 beta 2/alpha 3 beta 4 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 alpha 4 beta 2/alpha 3 beta 4 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 alpha 4 beta 2 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. (C) 2016 Elsevier Ltd. All rights reserved.