Synthesis of 3-aza[4.4.3]propellanes with high σ1 receptor affinity

Publication date: Available online 15 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Héctor Torres-Gómez, Constantin Daniliuc, Dirk Schepmann, Bernhard Wünsch
In order to obtain rigid σ1 receptor ligands with defined orientation of pharmacophoric elements, the azapropellane scaffold was chosen. Schmidt rearrangement of propellan-8-ones 6 and 10 provided 3-azapropellan-4-ones 7 and 11. Benzylation of the secondary lactams 7 and 11 followed by LiAlH4 reduction furnished the azapropellanes 4a and 4c, respectively. A second hydrophobic element was introduced by transformation of the alcohols 4a into carbamates 4b. The σ1 affinity of the azapropellanes 4 is strongly dependent on the stereochemistry and the substitution pattern in 12-position. anti-configured azapropellanes anti-4a and anti-4b show higher σ1 affinity than their syn-configured counterparts syn-4a and syn-4b. Conversion of the alcohol anti-4a into the carbamate anti-4b led to increased σ1 affinity, but complete removal of the 12-substituent resulted in the highest σ1 affinity (Ki(4c) = 17 nM). It can be concluded that the propellane scaffold alone is able to form strong lipophilic interactions and stabilize the ligand - σ1 receptor complex as does usually the primary hydrophobic region.

Graphical abstract

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