文摘
The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent 蟽1 receptor (蟽1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other 蟽1R ligands, showed high selectivity over the 蟽2 receptor (蟽2R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known 蟽1R 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 蟽1R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain.