An Interactive SAR Approach to Discover Novel Hybrid Thieno Probes as Ligands for D2‐Like Receptors with Affinities in the Subnanomolar Range. Issue 12 (December 2013)

• Record Type: Journal Article
• Authors: Abdel‐Fattah, Mohamed A. O.; Lehmann, Jochen; Abadi, Ashraf H.
• Is Part Of: Chemistry & biodiversity. Volume 10:Issue 12(2013:Dec.)
• Page Start: 2247
• Page End: 2266
• Publication Date: 2013-12
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Biodiversity -- Periodicals; 572
• DOI: 10.1002/cbdv.201300204
• Languages: English
• ISSNs: 1612-1872

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>A series of [(phenylpiperazinyl)alkyl]‐isoindole‐1, 3‐dione derivatives was synthesized to serve as probes for dopaminergic receptors. Among this series, compound <bold>6a</bold> showed the highest affinity towards D4 and D3 receptors with <italic>K</italic>_i values in the low nanomolar range, and D2/D4‐ and D2/D3‐selectivity indices of 72 and 20, respectively. Optimization rounds were adopted and led to the D4‐selective ligand thiophene‐2‐carboxamide <bold>9a</bold> with a <italic>K</italic>_i(D4) value of 0.62 n<sc>M</sc>, and to its butyl analog, <bold>10a</bold>, with <italic>K</italic>_i(D4) and <italic>K</italic>_i(D3) values of 0.03 and 0.26 n<sc>M</sc>, respectively. Docking experiments revealed the importance of the unique D4 residue Arg186 in manipulating the ligands' D4‐subtype‐receptor selectivity.</p> </abstract>