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S1P 1 (sphingosine-1-phosphate receptor 1) agonists prevent lymphocyte egress from secondary lymphoid organs and cause a reduction in the number of circulating blood lymphocytes. We hypothesized that S1P 1 receptor modulators with pathway-selective signaling properties could help to further elucidate the molecular mechanisms involved in lymphocyte trapping. A proprietary S1P 1 receptor modulator library was screened for compounds with clear potency differences in β -arrestin recruitment and G protein alpha i subunit (G  α   i ) protein-mediated signaling. We describe here the structure-activity relationships of highly potent S1P 1 modulators with apparent pathway selectivity for β -arrestin recruitment. The most differentiated compound, D3-2, displayed a 180-fold higher potency in the β -arrestin recruitment assay (EC 50 0.9 nM) compared with the G  α   i -activation assay (167 nM), whereas ponesimod, a S1P 1 modulator that is currently in advanced clinical development in multiple sclerosis, was equipotent in both assays (EC 50 1.5 and 1.1 nM, respectively). Using these novel compounds as pharmacological tools, we showed that although a high potency in β -arrestin recruitment is required to fully internalize S1P 1 receptors, the potency in inducing G  α   i signaling determines the rate of receptor internalization in vitro. In contrast to ponesimod, the compound D3-2 did not reduce the number or circulating lymphocytes in rats despite high plasma exposures. Thus, for rapid and maximal S1P 1 receptor internalization a high potency in both G  α   i signaling and β -arrestin recruitment is mandatory and this translates into efficient reduction of the number of circulating lymphocytes in vivo.

molecular pharmacology

S1P1 Modulator-Induced Gαi Signaling and β-Arrestin Recruitment Are Both Necessary to Induce Rapid and Efficient Reduction of Blood Lymphocyte Count In Vivo