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Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D3 Receptor (D3R) Ligand Promiscuity across Highly Conserved Aminergic G‑Protein-Coupled Receptors (GPCRs)

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journal contribution
posted on 25.04.2019, 00:00 by Sean W. Reilly, Aladdin A. Riad, Chia-Ju Hsieh, Kristoffer Sahlholm, Daniel A. Jacome, Suzy Griffin, Michelle Taylor, Chi-Chang Weng, Kuiying Xu, Nathan Kirschner, Robert R. Luedtke, Christopher Parry, Shipra Malhotra, John Karanicolas, Robert H. Mach
Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)­thio)­propyl)-3,9-diazaspiro­[5.5]­undecane (1) compound with excellent dopamine D3 receptor (D3R) affinity (D3R Ki = 12.0 nM) and selectivity (D2R/D3R ratio = 905). Herein, we present derivatives of 1 with comparable D3R affinity (32, D3R Ki = 3.2 nM, D2R/D3R ratio = 60) and selectivity (30, D3R Ki = 21.0 nM, D2R/D3R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D3R affinity (Ki = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D3R Ki = 23.9 nM), 1 was found to be more selective for the D3R among D1- and D2-like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D3R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D3R ligand systems to minimize drug promiscuity at other aminergic GPCR sites.