The preparation of polystyrene−divinylbenzene-supported derivatives of tris(2-aminoethyl)amine and methyl isocyanate are described. These polymeric reagents are used to quench excess reactants and remove known impurities from the crude reaction products obtained from the solution-phase, parallel syntheses of ureas, thioureas, sulfonamides, amides, and pyrazoles. In conjunction with the use of other polymeric reactants during the course of a reaction, the addition of polymer-supported quench reagent(s) at the conclusion of the reaction allows isolation of the desired product by a single filtration and evaporation of solvent. The mechanical simplicity and efficiency of this methodology make possible the rapid, parallel purification of crude reaction products obtained via solution-phase syntheses, regardless of whether the intended product is a single compound or a mixture of compounds, and hence offers an attractive alternative to solid-phase organic synthesis in the practice of combinatorial chemistry.

Structure-activity relationships are reported for a novel class of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid derivatives that displace 125I-labeled angiotensin II from a specific subset of angiotensin II (Ang II) binding sites in rat adrenal preparations. This binding site is not the Ang II receptor mediating vascular contraction or aldosterone release, but, rather, is one whose function has not yet been fully elucidated. It has been identified in a number of tissues and has a similar affinity for Ang II and its peptide analogues as does the vascular receptor. The non-peptide compounds reported here are uniquely specific in displacing Ang II at this binding site and are inactive in antagonizing Ang II at the vascular receptor or in pharmacological assays measuring vascular effects. PD 123,319 (79), one of the most potent compounds, has an IC50 of 34 nM. Certain of these compounds may have utility in the definition and study of Ang II receptor subtypes.

Angiotensin II (Ang II) receptors, estimated by the specific binding of the peptide Ang II receptor antagonist [125I] [Sar1,Ile8]Ang II, are localized on multiple ovarian structures, including follicular granulosa cells. Using the Ang II receptor subtype-selective nonpeptide antagonists, DuP 753 [selective for the type 1 Ang II (AT1) receptor] and PD 123319 [selective for the type 2 Ang II (AT2) receptor], we show that follicular granulosa cells, in vivo and in vitro, exclusively express the AT2 receptor. To understand the function of Ang II in ovarian follicles, we compared the biochemical properties and transmembrane signaling pathways of the granulosa cell AT2 receptor with those properties generally associated with Ang II receptors found in the adrenal zona glomerulosa, where the AT1 receptor predominates. The mol wt of the granulosa cell AT2 receptor (approximately 79,000), estimated by affinity cross-linking studies, is similar to that of the adrenal zona glomerulosa Ang II receptor. Like the adrenal zona glomerulosa Ang II receptor, binding inhibition studies show that the granulosa cell AT2 receptor binds Ang II and Ang III with high affinity (IC50, approximately 0.5 nM for both peptides), but not Ang-(1-7) (IC50, approximately 0.5 microM) or Ang-(1-5) (IC50, greater than 10 microM). However, unlike the adrenal zona glomerulosa Ang II receptor, the granulosa cell AT2 receptor does not undergo agonist-induced endocytosis. Further, Ang II does not affect basal or stimulated inositol phosphate production, intracellular Ca2+ mobilization, or adenylyl cyclase or guanylyl cyclase activity in granulosa cells. The granulosa cell AT2 receptor does not appear to directly interact with guanine nucleotide binding regulatory proteins, since agonist dissociation from the AT2 receptor is unaffected by the GTP analog guanosine 5'-O-(3-thiotriphosphate); in contrast, the AT1 receptor appears to directly interact with guanine nucleotide binding regulatory protein, because agonist dissociation from the AT1 receptor is stimulated by guanosine 5'-O-(3-thiotriphosphate). These studies clearly demonstrate that the granulosa cell AT2 receptor is functionally distinct from the well characterized adrenal zona glomerulosa Ang II receptor. The exclusive presence of the AT2 receptor on the granulosa cell makes it an ideal cell type for studying the potential, but as yet unknown, function of this receptor.

Merrifield resin is converted to a solid-supported free radical initiator by reacting with the TEMPO-Na. Heating TEMPO-methyl resin with a variety of functionalized styrene and acrylate monomers gives larger resin beads via living free radical polymerization. We have coined the term Rasta resin to describe resin beads prepared in this fashion. The process can be described as a solvent-free suspension polymerization. It is particularly well suited for preparation of resin beads from monomers which contain electrophilic groups that would be destroyed upon suspension polymerization in water. Rasta resins have a novel macromolecular architecture wherein long straight chain polymers bearing reactive functional groups emanate from the phenyl groups of a cross-linked polystyrene core. With judicious choice of co-monomers and polymerization strategy, the solvent affinity, loading capacity, and distance of functionality from the cross-linked core may be controlled giving beads with properties that are tailored to specific uses as synthesis supports and scavenging resins.

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