RT Journal Article
SR Electronic
T1 S1P1 Modulator-Induced Gαi Signaling and β-Arrestin Recruitment Are Both Necessary to Induce Rapid and Efficient Reduction of Blood Lymphocyte Count In Vivo
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 109
OP 118
DO 10.1124/mol.117.109140
VO 93
IS 2
A1 Magdalena Birker-Robaczewska
A1 Martin Bolli
A1 Markus Rey
A1 Ruben de Kanter
A1 Christopher Kohl
A1 Cyrille Lescop
A1 Maxime Boucher
A1 Sylvie Poirey
A1 Beat Steiner
A1 Oliver Nayler
YR 2018
UL http://molpharm.aspetjournals.org/content/93/2/109.abstract
AB S1P1 (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 S1P1 receptor modulators with pathway-selective signaling properties could help to further elucidate the molecular mechanisms involved in lymphocyte trapping. A proprietary S1P1 receptor modulator library was screened for compounds with clear potency differences in β-arrestin recruitment and G protein alpha i subunit (Gαi) protein-mediated signaling. We describe here the structure-activity relationships of highly potent S1P1 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 (EC50 0.9 nM) compared with the Gαi-activation assay (167 nM), whereas ponesimod, a S1P1 modulator that is currently in advanced clinical development in multiple sclerosis, was equipotent in both assays (EC50 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 S1P1 receptors, the potency in inducing Gαi 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 S1P1 receptor internalization a high potency in both Gαi signaling and β-arrestin recruitment is mandatory and this translates into efficient reduction of the number of circulating lymphocytes in vivo.