1 research outputs found
Synthesis and Biological Evaluation of a New Series of Hexahydro‑2<i>H</i>‑pyrano[3,2‑<i>c</i>]quinolines as Novel Selective σ<sub>1</sub> Receptor Ligands
The
synthesis and pharmacological activity of a new series of hexahydro-2<i>H</i>-pyrano[3,2-<i>c</i>]quinoline derivatives as
potent σ<sub>1</sub> receptor (σ<sub>1</sub>R) ligands
are reported. This family, which does not contain the highly basic
amino group usually present in other σ<sub>1</sub>R ligands,
showed high selectivity over the σ<sub>2</sub> receptor (σ<sub>2</sub>R). The activity was shown to reside in only one of the four
possible diastereoisomers, which exhibited a perfect match with known
σ<sub>1</sub>R pharmacophores. A hit to lead program based on
a high-throughput screening hit (<b>8a</b>) led to the identification
of compound <b>32c</b>, with substantially improved activity
and physicochemical properties. Compound <b>32c</b> also exhibited
a good ADMET (absorption, distribution, metabolism, excretion, toxicity)
profile and was identified as a σ<sub>1</sub>R antagonist on
the basis of its analgesic activity in the mouse capsaicin and formalin
models of neurogenic pain