Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS.

Acid-sensing ion channels (ASICs) are a family of ion channels permeable to cations and largely responsible for the onset of acid-evoked ion currents both in neurons and in different types of cancer cells, thus representing a potential target for drug discovery. Owing to the limited attention ASIC2 has received so far, an exploratory program was initiated to identify ASIC2 inhibitors using diminazene, a known pan-ASIC inhibitor, as a chemical starting point for structural elaboration. The performed exploration enabled the identification of a novel series of ASIC2 inhibitors. In particular, compound 2u is a brain penetrant ASIC2 inhibitor endowed with an optimal pharmacokinetic profile. This compound may represent a useful tool to validate in animal models in vivo the role of ASIC2 in different neurodegenerative central nervous system pathologies.

Synthesis and biological evaluation of 1,3-dioxolane-based 5-HT1A receptor agonists for CNS disorders and neuropathic pain.

AIM: Targeting 5-HT1A receptor (5-HT1AR) as a strategy for CNS disorders and pain control. METHODOLOGY: A series of 1,3-dioxolane-based 2-heteroaryl-phenoxyethylamines was synthesized by a convergent approach and evaluated at α1-adrenoceptors and 5-HT1AR by binding and functional experiments. Absorption, distribution, metabolism, excretion and toxicity prediction studies were performed to explore the drug-likeness of the compounds. RESULTS & CONCLUSION: The most promising compound, the pyridin-4-yl derivative, emerged as a potent and selective 5-HT1AR agonist (pKi = 9.2; pD2 = 8.83; 5-HT1A/α1 = 135). In vitro it was able to permeate by passive diffusion MDCKII-MDR1 monolayer mimicking the blood-brain barrier and showed promising neuroprotective activity.

Structure-Activity Relationships within a Series of σ1 and σ2 Receptor Ligands: Identification of a σ2 Receptor Agonist (BS148) with Selective Toxicity against Metastatic Melanoma.

A new series of spirocyclic σ receptor (σR) ligands were prepared and studied. Most were found to have a high affinity and selectivity for σ1 R; three compounds were shown to be σ1 R agonists, while another proved to be the only σ1 R antagonist. Only one of the σ1 R agonists (BS148) also exhibited σ2 R selectivity and was able to inhibit the growth of metastatic malignant melanoma cell lines without affecting normal human melanocytes. The antiproliferative activity of this compound suggested an σ2 R agonist profile. Further, preliminary investigations indicated that the mechanism of metastatic malignant melanoma cell death induced by BS148 is due, at least in part, to apoptosis.