title: Escape from adamantane: Scaffold optimization of novel P2X7 antagonists featuring complex polycycles.
abstract: The adamantane scaffold, despite being widely used in medicinal chemistry, is not devoid of problems. In recent years we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As an adamantane scaffold is a common structural feature in several P2X7 receptor antagonists, herein we report the synthesis and pharmacological evaluation of multiple replacement options of adamantane that maintain a good activity profile. Molecular modeling studies support the binding of the compounds to a site close to the central pore, rather than to the ATP-binding site and shed light on the structural requirements for novel P2X7 antagonists.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, Barcelona E-08028, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Barniol-Xicota
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors.forename: Seung-Hwa
authors.initials: SH
authors.lastname: Kwak
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors.forename: So-Deok
authors.initials: SD
authors.lastname: Lee
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Caseley
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, Barcelona E-08028, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Valverde
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom.
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Jiang
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea. Electronic address: yongchul@gist.ac.kr.
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, Barcelona E-08028, Spain. Electronic address: svazquez@ub.edu.
authors.forename: Santiago
authors.initials: S
authors.lastname: Vázquez
mesh_terms: D000218:Adamantane / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D058920:Purinergic P2X Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D000218:Adamantane
keywords: Adamantane; Drug discovery; Homology models; P2X7 antagonists; Scaffold replacement