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

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 D receptor (DR) affinity (DR K = 12.0 nM) and selectivity (DR/DR ratio = 905). Herein, we present derivatives of 1 with comparable DR affinity (32, DR K = 3.2 nM, DR/DR ratio = 60) and selectivity (30, DR K = 21.0 nM, DR/DR ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low DR affinity ( K = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, DR K = 23.9 nM), 1 was found to be more selective for the DR among D- and D-like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing DR scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into DR ligand systems to minimize drug promiscuity at other aminergic GPCR sites.