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Vol. 59, Issue 5, 1206-1215, May 2001

Structural Determinants of Adenophostin A Activity at Inositol Trisphosphate Receptors

Vanessa Correa, Andrew M. Riley, Satoshi Shuto, Graeme Horne, Edmund P. Nerou, Rachel D. Marwood, Barry V. L. Potter, and Colin W. Taylor

Department of Pharmacology, University of Cambridge, Cambridge, CB2 1QJ, United Kingdom (V.C., E.P.N., C.W.T.); and Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom (A.M.R., S.S., G.H., R.D.M., B.V.L.P.)

Adenophostin A is the most potent known agonist of inositol 1,4,5-trisphosphate (InsP3) receptors. Ca2+ release from permeabilized hepatocytes was 9.9 ± 1.6-fold more sensitive to adenophostin A (EC50, 14.7 ± 2.4 nM) than to InsP3 (145 ± 10 nM), consistent with the greater affinity of adenophostin A for hepatic InsP3 receptors (Kd = 0.48 ± 0.06 and 3.09 ± 0.33 nM, respectively). Here, we systematically modify the structures of the glucose, ribose, and adenine moieties of adenophostin A and use Ca2+ release and binding assays to define their contributions to high-affinity binding. Progressive trimming of the adenine of adenophostin A reduced potency, but it fell below that of InsP3 only after complete removal of the adenine. Even after substantial modifications of the adenine (to uracil or even unrelated aromatic rings, retaining the beta -orientation), the analogs were more potent than InsP3. The only analog with an alpha -ribosyl linkage had massively decreased potency. The 2'-phosphate on the ribose ring of adenophostin A was essential and optimally active when present on a five-membered ring in a position stereochemically equivalent to its location in adenophostin A. Xylo-adenophostin, where xylose replaces the glucose ring of adenophostin A, was only slightly less potent than adenophostin A, whereas manno-adenophostin (mannose replacing glucose) had similar potency to InsP3. These results are consistent with the relatively minor role of the 3-hydroxyl of InsP3 (the equivalent is absent from xylo-adenophostin) and greater role of the equatorial 6-hydroxyl (the equivalent is axial in manno-adenophostin). This is the first comprehensive analysis of all the key structural elements of adenophostin A, and it provides a working model for the design of related high-affinity ligands of InsP3 receptors.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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