Synthesis and Biological Evaluation of a New Series of Hexahydro-2H-pyrano[3,2-c]quinolines as Novel Selective σ₁ Receptor Ligands

Abstract

The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]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 (8a) led to the identification of compound 32c, with substantially improved activity and physicochemical properties. Compound 32c 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.

Investigational sigma-1 receptor antagonists for the treatment of pain

“…A series of quinoline s 1 R ligands, showing high selectivity over the s 2 R receptor, was identified following an HTS screening campaign. Although the initial hit was highly lipophilic, the hit to lead program led to the identification of compound 25, which showed a substantial improvement in activity and solubility, and good analgesia in the mouse capsaicin and formalin models of neurogenic pain [87,88]. Finally, the latest patents in the field describe a series of imidazothiazoles represented by 26 [89] and two related families of pyrazinoindole derivatives, 27 [90] and 28 [91].…”

4-Hydroxyquinolin-2-ones and their Close Structural Analogues as a New Source of Highly Effective Pain-Killers

“…Besides, isolation of biologically active substances from the plant or animal raw material, their subsequent purification and standardization is, as a rule, difficult and time-consuming. That is why it is quite natural that the search of new analgesics of the quinoline Internet resources reveals a lot of publications concerning the given topics [17][18][19][20][21][22][23]. Thus, promising substances are created based on various derivatives both quinoline (3) itself and its hydrogenized analogs (4).…”

Optimization of the Antiviral Potency and Lipophilicity of Halogenated 2,6‐Diarylpyridinamines as a Novel Class of HIV‐1 NNRTIS

“…Therefore, molecular lipophilicity has recently been considered as a major factor in the quality of a drug candidate. To balance potency and lipophilicity related to multiple drug-like properties, the concepts of ligand efficiency (LE), lipophilic ligand efficiency (LLE), [15] and ligand efficiency dependent lipophilicity (LELP) [16] have been accepted and applied [17-19] as usefully predictive tools to aid in decision making. Accordingly, we further assessed drug-like properties and predicted parameters for these new active DAPAs in parallel with 2b and 1b as shown in Table 3.…”