- 4-alkyloxyimino derivatives of uridine-5′-triphosphate: Distal modification of potent agonists as a strategy for molecular probes of P2Y 2, P2Y4, and P2Y6 receptors
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Extended N4-(3-arylpropyl)oxy derivatives of uridine-5′-triphosphate were synthesized and potently stimulated phospholipase C stimulation in astrocytoma cells expressing G protein-coupled human (h) P2Y receptors (P2YRs) activated by UTP (P2Y2/4R) or UDP (P2Y6R). The potent P2Y4R-selective N4-(3- phenylpropyl)oxy agonist was phenyl ring-substituted or replaced with terminal heterocyclic or naphthyl rings with retention of P2YR potency. This broad tolerance for steric bulk in a distal region was not observed for dinucleoside tetraphosphate agonists with both nucleobases substituted. The potent N 4-(3-(4-methoxyphenyl)-propyl)oxy analogue 19 (EC50: P2Y2R, 47 nM; P2Y4R, 23 nM) was functionalized for chain extension using click tethering of fluorophores as prosthetic groups. The BODIPY 630/650 conjugate 28 (MRS4162) exhibited EC50 values of 70, 66, and 23 nM at the hP2Y2/4/6Rs, respectively, and specifically labeled cells expressing the P2Y6R. Thus, an extended N4-(3- arylpropyl)oxy group accessed a structurally permissive region on three G q-coupled P2YRs, and potency and selectivity were modulated by distal structural changes. This freedom of substitution was utilized to design of a pan-agonist fluorescent probe of a subset of uracil nucleotide-activated hP2YRs.
- Jayasekara, P. Suresh,Barrett, Matthew O.,Ball, Christopher B.,Brown, Kyle A.,Hammes, Eva,Balasubramanian, Ramachandran,Harden, T. Kendall,Jacobson, Kenneth A.
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p. 3874 - 3883
(2014/05/20)
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- AMINE COMPOUND AND PHARMACEUTICAL USE THEREOF
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Provided is a novel amine compound represented by the following formula (I) having a superior peripheral blood lymphocyte decreasing action and superior in the immunosuppressive action, rejection suppressive action and the like, which shows decreased side effects of, for example, bradycardia and the like, or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof, or a solvate thereof. wherein each symbol is as defined in the specification.
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Page/Page column 182
(2010/04/25)
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- Iodoaryl analogues of dioctanoylglycerol and 1-oleoyl-2-acetylglycerol as probes for protein kinase C
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Analogues of dioctanoylglycerol (diC8) and 1-oleoyl-2-acetylglycerol (OAG) containing an iodoaryl group have been synthesized and shown to compete with [3H]phorbol dibutyrate ([3H]PDBu) for binding to protein kinase C in a crude rat brain preparation. Phorbol diesters have been shown to bind specifically to protein kinase C and the PDBu receptor has been copurified with protein kinase C activity. All three diacylglycerol analogues were comparable to OAG in binding affinity. In an assay of protein kinase C activation, the diC8 analogue was more active than the OAG analogues, thus demonstrating greater structural specificity under the conditions of this assay.
- Strawn,Martell,Simpson,Leach,Counsell
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p. 2104 - 2110
(2007/10/02)
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