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13.
Histidine 6.55 Is a Major Determinant of Ligand-Biased Signaling in Dopamine D2L Receptor
Tschammer, Nuška ...
In our previous studies, we demonstrated that the mutation of His3936.55 to alanine results in an increased affinity of 1,4-disubstituted phenylpiperazines to the dopamine D2L receptor. This change ...most likely accounts for the reduced steric hindrance in this part of the binding pocket. In this work, we investigated the role of the steric hindrance imposed by the residue His3936.55 for the receptor activation modulated by 1,4-disubstituted aromatic piperidines/piperazines. Site-directed mutagenesis and ligand modifications were used to probe the structural basis of ligand efficacy. The operational model of agonism was used to quantify the ligand bias between the ability of compounds to inhibit cAMP accumulation and stimulate extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Whereas substantial ligand-biased signaling was observed for the D2L wild-type receptor, an overall increase in agonism was observed for the D2L H3936.55A mutant without noteworthy functional selectivity. Targeted chemical modification of the phenylpiperazine moiety at the site of its interaction with the residue His3936.55 led to the functionally selective ligand {3-[4-(2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-propyl}-pyrazol[1,5-a]pyridine-3-carboxamide (FAUC350) that has distinct signaling profiles toward adenylyl cyclase and ERK1/2. FAUC350 behaves as an antagonist in the inhibition of cAMP accumulation and as a partial agonist in the stimulation of ERK1/2 phosphorylation (efficacy = 55%). Overall, the residue His3936.55 and proximate molecular substructures of receptor ligands were identified to be crucial for multidimensional ligand efficacy.
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