Predicting the Antinociceptive Efficacy of σ₁ Receptor Ligands by a Novel Receptor Fluorescence Resonance Energy Transfer (FRET) Based Biosensor

We have developed a novel methodology for monitoring the σ₁ receptor activation switch in living cells. Our assay uncovered the intrinsic nature of σ₁ receptor ligands by recording the ligand-mediated conformational changes of this chaperone protein. The change triggered by each ligand correlated well with its ability to attenuate formalin induced nociception in an animal model of pain. This tool may assist in predicting the antinociceptive efficacy of σ₁ receptor ligands

Synthesis and Structure–Activity Relationship Study of a New Series of Selective σ₁ Receptor Ligands for the Treatment of Pain: 4‑Aminotriazoles

The synthesis and pharmacological activity of a new series of 4-aminotriazoles as potent σ₁ receptor (σ₁R) ligands are reported. The compounds were prepared using a 4–5-step process, involving as a key step a click chemistry reaction between ynamides and azides. The most active compounds exhibited nanomolar potency for the σ₁R, and the selectivity over the σ₂R was improved on decreasing the central amine basicity. It was concluded that in order to achieve good σ₁R potency a minimum lipophilicity was required, while limiting to a defined range of cLog<i>P</i> avoided human ether-a-go-go-related gene channel inhibition. This made the most interesting derivatives to be concentrated in a narrow margin of lipophilicity. Among them, compound <b>13g</b> exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character

Synthesis and Biological Evaluation of the 1‑Arylpyrazole Class of σ₁ Receptor Antagonists: Identification of 4‑{2-[5-Methyl-1-(naphthalen-2-yl)‑1<i>H</i>‑pyrazol-3-yloxy]ethyl}morpholine (S1RA, E‑52862)

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ₁ receptor (σ₁R) antagonists are reported. The new compounds were evaluated in vitro in human σ₁R and guinea pig σ₂ receptor (σ₂R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ₁R vs σ₂R. The most selective compounds were further profiled, and compound <b>28</b>, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1<i>H</i>-pyrazol-3-yloxy]­ethyl}­morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound <b>28</b> exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound <b>28</b> to be selected as clinical candidate

Synthesis and Biological Evaluation of a New Series of Hexahydro‑2<i>H</i>‑pyrano[3,2‑<i>c</i>]quinolines as Novel Selective σ₁ 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 σ₁ receptor (σ₁R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ₁R ligands, showed high selectivity over the σ₂ receptor (σ₂R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ₁R 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 σ₁R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain