(Aminoalkoxy)chromones. Selective sigma receptor ligands

Area of Science:

• Medicinal Chemistry
• Neuropharmacology
• Drug Discovery

Background:

• Sigma binding sites and dopamine D2 receptors are critical targets in neuroscience.
• Developing selective ligands for these receptors is crucial for therapeutic interventions.

Purpose of the Study:

• To synthesize and characterize novel (aminoalkoxy)chromone derivatives.
• To evaluate their binding affinities at sigma and dopamine D2 receptors.
• To assess their potential as antipsychotic agents and in ischemia models.

Main Methods:

• Synthesis of a series of (aminoalkoxy)chromone compounds.
• In vitro receptor binding assays to determine affinities at sigma and dopamine D2 receptors.
• In vivo behavioral studies in animal models predictive of antipsychotic activity and ischemia.

Main Results:

• The synthesized (aminoalkoxy)chromones exhibited potent binding at the sigma site (16-100 nM) and weak binding at the dopamine D2 receptor (>1000 nM).
• Optimal side chain attachment was observed at the 7-position of the chromone ring.
• Non-coplanar 2-substituents enhanced binding affinity.
• Compound 74 showed high affinity for sigma sites and low affinity for D2 receptors.
• Compound 58 demonstrated significant selectivity for sigma sites over D2 receptors.
• Compound 44 (NPC 16377) showed systemic efficacy in antipsychotic and ischemia models.

Conclusions:

• The (aminoalkoxy)chromone scaffold is a promising platform for developing selective sigma receptor ligands.
• These compounds hold potential for the treatment of psychosis and ischemia-related conditions.
• Further investigation into their therapeutic applications is warranted.