Bicyclic Diazepinones as Dual Ligands of the α2δ‑1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter
journal contributionposted on 16.02.2021, 19:54 by José Luis Díaz, Félix Cuevas, Gonzalo Pazos, Paula Álvarez-Bercedo, Ana I. Oliva, M. Ángeles Sarmentero, Daniel Font, Agustín Jiménez-Aquino, María Morón, Adriana Port, Rosalía Pascual, Albert Dordal, Enrique Portillo-Salido, Raquel F. Reinoso, José Miguel Vela, Carmen Almansa
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.
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NET pharmacophoresNorepinephrine Transporter2- ethylamino -9-methyl H3- methylamino -1-thiophenylpropoxy...NET functionalityAlternative bicyclic frameworksVoltage-Gated Calcium Channelsattachment3- methylamino -1-phenylpropoxynorepinephrine transporterADMET propertiesα2δ-1 subunitphenyl ringDual Ligandsvoltage-gated calcium channelsv α2δ-1 scaffoldBicyclic Diazepinonesbicyclic diazepinones