BML‐241 fails to display selective antagonism at the sphingosine‐1‐phosphate receptor, S1P3

Background and purpose: The thiazolidine carboxylic acid, BML‐241, has been proposed as a lead compound in development of selective antagonists at the sphingosine‐1‐phosphate receptor (S1P3), based on its inhibition of the rise in intracellular calcium concentrations ([Ca2+]i) in HeLa cells overexpr...

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Bibliographic Details
Published in:British journal of pharmacology 2006-10, Vol.149 (3), p.277-282
Main Authors: Jongsma, M, Hendriks‐Balk, M C, Michel, M C, Peters, S L M, Alewijnse, A E
Format: Article
Language:English
Subjects:
Biological and medical sciences
BML‐241
Medical sciences
Pharmacology. Drug treatments
Research Papers
S1P receptor
S1P3 antagonist
sphingosine‐1‐phosphate
α1‐adrenoceptor
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Summary:Background and purpose: The thiazolidine carboxylic acid, BML‐241, has been proposed as a lead compound in development of selective antagonists at the sphingosine‐1‐phosphate receptor (S1P3), based on its inhibition of the rise in intracellular calcium concentrations ([Ca2+]i) in HeLa cells overexpressing S1P receptors. We have studied the antagonistic properties of BML‐241 for the S1P3 receptor in more detail. Experimental approach: Chinese hamster ovary (CHO) cells stably transfected with the S1P3, S1P2 or α1A‐adrenoceptors were used to investigate the effect of BML‐241 on increases in [Ca2+]i mediated via different receptors. CHO‐K1 cells were used to study ATP‐induced [Ca2+]i elevations. Effects on S1P3‐mediated inhibition of forskolin‐induced cAMP accumulation and on binding to α1A‐adrenoceptors were also investigated. In addition, the effect of BML‐241 on contractions of rat mesenteric artery induced by phenylephrine was studied in an organ bath. Key results: High concentrations of BML‐241 (10 μM) inhibited the rise in [Ca2+]i induced by S1P3 and S1P2 receptor stimulation; lower concentrations were ineffective. This high concentration of BML‐241 also inhibited [Ca2+]i increases via P2 (nucleotide) receptor or α1A‐adrenoceptor stimulation. Moreover, BML‐241 (10 μM) inhibited α1‐adrenoceptor‐mediated contraction of rat mesenteric artery but did not displace [3H]‐prazosin from α1A‐adrenoceptors in concentrations up to 100 μM. BML‐241 (10 μM) did not affect the S1P3‐mediated decrease of forskolin‐induced cAMP accumulation. Conclusions and Implications: We conclude that BML‐241 is a low potency, non‐selective inhibitor of increases in [Ca2+]i, rather than a specific antagonist at the S1P3 receptor. British Journal of Pharmacology (2006) 149, 277–282. doi:10.1038/sj.bjp.0706872
ISSN:0007-1188
1476-5381
DOI:10.1038/sj.bjp.0706872