Structural optimization and anticonvulsant evaluation of aminoalkyl indole derivatives

A series of twenty-two novel aminoalkyl indole derivatives were rationally designed and synthesized via Friedel-Crafts acylation followed by nucleophilic substitution, targeting the cannabinoid receptor 2 (CB2R) as a novel approach for anticonvulsant therapy. Systematic structural optimization of the indole C-3 cycloheptanecarbonyl moiety and the N-1 aminoalkyl side chain was conducted to balance CB2R affinity, subtype selectivity, lipophilicity, and blood-brain barrier (BBB) permeability. In vitro pharmacological characterization identified compound 6d as a potent and selective CB2R agonist (EC₅₀ = 4.00 nM), with approximately 46-fold functional selectivity over CB1 receptors. In the subcutaneous pentylenetetrazole (scPTZ) seizure model, compound 6d demonstrated favorable anticonvulsant efficacy (ED₅₀ = 21.28 mg/kg, i.p.) with a high protective index (PI = 21.28), comparing favorably with the reference drug carbamazepine in both potency and safety margin. Compound 6d also exhibited favorable pharmacokinetic properties, including moderate BBB permeability (PAMPA-BBB), acceptable metabolic stability in mouse liver microsomes, sufficient brain-to-plasma exposure ratios, and negligible cytotoxicity in HepG2 cells at therapeutic concentrations. Additionally, analogue 6 g displayed moderate activity in the maximal electroshock (MES) model with a favorable safety profile. These findings indicate that the cycloheptanecarbonyl-indole scaffold represents a valuable lead structure for the development of brain-permeable, selective CB2R-targeted antiepileptic agents.