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The synthesis and pharmacological activity of a new series of thieno[2,3- d ]pyrimidin-4(3 H )-one derivatives as sigma-1 receptor (σ 1 R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ 1 R agonist ( 14qR ) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ 1 R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ 1 R association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.

The synthesis and pharmacological activity of a new series of isoxazolylpyrimidines as sigma-2 receptor (σ 2 R) ligands are reported. Modification of a new hit retrieved in an HTS campaign allowed the identification of the compound WLB-89462 ( 20c ) with good σ 2 R affinity ( K i = 13 nM) and high selectivity vs both the σ 1 R ( K i = 1777 nM) and a general panel of 180 targets. It represents one of the first σ 2 R ligands with drug-like properties, linked to a good physicochemical and ADMET profile (good solubility, no CYP inhibition, good metabolic stability, high permeability, brain penetration, and high oral exposure in rodents). Compound 20c shows neuroprotective activity in vitro and improves short-term memory impairment induced by hippocampal injection of amyloid β peptide in rats. Together with the promising effects in the chronic models where 20c is currently being evaluated, these results pave the way toward its clinical development as a neuroprotective agent.

A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ 1 receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, 18g , showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.

The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ 1 receptor (σ 1 R) and the μ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles. Compound 14u (EST73502) showed MOR agonism and σ 1 R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ 1 R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.

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.