Bicyclic Diazepinones as Dual Ligands of the α2δ‑1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter

The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Cavα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5H-pyrimido­[4,5-e]­[1,4]­diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality. Alternative bicyclic frameworks were also explored, and some lead molecules were identified, which showed a balanced dual profile and exhibited good ADMET properties.

本研究报道了一类新型双环二氮杂卓酮类化合物的合成及其药理学活性，该类化合物对电压门控钙通道α2δ-1亚基（Cavα2δ-1）与去甲肾上腺素转运体（NET）具有双重靶向活性。通过对非氨基酸类Cavα2δ-1骨架上适宜取代位点的系统探索，明确了连接NET药效团的优选位点。在所考察的取代模式中，将2-乙基氨基-9-甲基-6-苯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮骨架连接至3-甲基氨基-1-苯丙氧基与3-甲基氨基-1-噻吩丙氧基基团的苯环间位时，所得双重活性化合物展现出优异的NET功能调控活性。本研究同时对其他双环骨架进行了探索，最终筛选得到数种先导化合物，这些化合物兼具平衡的双重活性谱，且表现出良好的ADMET（吸收、分布、代谢、排泄、毒性）特性。