Document Report Card

ID: ALA4396871

Journal: J Med Chem

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

Authors: Reilly SW, Riad AA, Hsieh CJ, Sahlholm K, Jacome DA, Griffin S, Taylor M, Weng CC, Xu K, Kirschner N, Luedtke RR, Parry C, Malhotra S, Karanicolas J, Mach RH.

Abstract: Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4 H-1,2,4-triazol-3-yl)thio)propyl)-3,9-diazaspiro[5.5]undecane (1) compound with excellent dopamine D₃ receptor (D₃R) affinity (D₃R K_i = 12.0 nM) and selectivity (D₂R/D₃R ratio = 905). Herein, we present derivatives of 1 with comparable D₃R affinity (32, D₃R K_i = 3.2 nM, D₂R/D₃R ratio = 60) and selectivity (30, D₃R K_i = 21.0 nM, D₂R/D₃R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D₃R affinity ( K_i = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D₃R K_i = 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.

CiteXplore: 31021617

DOI: 10.1021/acs.jmedchem.9b00412