New lead elements for histamine H3 receptor ligands in the pyrrolo[2,3-d]pyrimidine class |
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Authors: | Christian Espinosa-Bustos Annika Frank Sandra Arancibia-Opazo Cristian O Salas Angelica Fierro Holger Stark |
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Institution: | 1. Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Santiago 6094411, Chile;2. Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, Germany;3. Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Santiago, Chile |
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Abstract: | This work describes the microwave assisted synthesis of twelve novel histamine H3 receptor ligands. They display pyrrolo2,3-d]pyrimidine derivatives with rigidized aliphatic amines as warheads. The compounds were screened for H3R and H4R binding affinities in radioligand displacement assays and the most potent compounds were evaluated for H3R binding properties in vitro and in docking studies. The combination of a rigidized H3R warhead and the pyrrolo2,3-d]pyrimidine scaffold resulted in selective activity at the H3 receptor with a pKi value of 6.90 for the most potent compound. A bipiperidine warhead displayed higher affinity than a piperazine or morpholine motif, while a naphthyl moiety in the arbitrary region increased affinity compared to a phenyl derivative. The compounds can be starting points for novel, simply synthesized histamine H3 receptor ligands. |
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Keywords: | Microwave assisted synthesis G-protein coupled receptors |
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