PIP couples

This term indicates a receptor ligand having different intrinsic activities at different transduction pathways coupled to a single receptor. To quote Urban et al. (2006 JPET, 104463 PiP) and Kenakin (2007 Trends Pharmacol Sci 28 359-361) the term biased agonism can be considered as a synonym of collateral efficacy, ... 

Neutrophil membranes contain inositol lipids, which comprise about 5-6% of the total membrane lipids. About 80% of these inositol lipids possess stearic acid (Cl8 0) at Cl and arachidonic acid (C20 4) at C2 positions. Phosphatidylinositol accounts for most of these lipids (90%), with smaller amounts of PIP (6%) and PIP 2 (4%), which are synthesised sequentially by the action of 4- and 5-specific kinases, respectively (see Fig. 6.6). Neutrophil membranes also possess a phosphatidylinositol-specific phospholipase C which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into Ins 1,4,5 P3 and DAG (Fig. 6.7). Both PLC-/3(/ 2) and PLC-y (72) families appear to be present in neutrophils. The coupling of receptor occupancy to PLC activation in neutrophils can be through a heterotrimeric G-protein, the mobile subunit of which has been termed G p. Evidence for this G-protein link comes from the following facts ... 

In solution-phase peptide synthesis, acylation of amino acids or peptides with N-protected azetidine-2-carboxylic acid is performed via the active esters, e.g. A-hydroxysuccin-imide 100 111-112 or pentachlorophenyl ester, m 117 as well as by the mixed anhydride 101114 or carbodiimide 118 methods. An attempt to prepare the A-carbonic acid anhydride by cycli-zation of A-(chloroformyl)azetidine-2-carboxylic acid with silver oxide in acetone or by addition of triethylamine in situ failed, presumably due to steric hindrance. 111 In SPPS, activation of the Fmoc-protected imino acid by HBTU 119,120 is reported. In solution-phase peptide synthesis, coupling of N-protected amino acids or peptides to C-protected azetidine-2-carboxylic acid or related peptides may be performed by active esters, 100 118 121 mixed anhydrides, 95 or similar methods. It may be worth mentioning that the probability of pip-erazine-2,5-dione formation from azetidine-2-carboxylic acid dipeptides is significantly reduced compared to proline dipeptides. 111 ... 

Fig. 2. A schematic representation of some of the mechanisms by which Car fluxes across the plasma membrane are regulated. In the plasma membrane (the striped area) there are both influx (=>) and energy-dependent ( ) efflux pathways. Two mechanisms by which Ca2+ influx can be increased are via the actions of the intracellular messengers inositol 1,3,4,5-tetrakisphosphate, and cAMP generated via activation of specific classes of surface receptors (R, and R2) linked to specific N proteins which activate either phosphatidylinositol 4,5-bisphosphate (PIP,) hydrolysis or adenylate cyclase (AC). Additionally, influx can be increased either by a direct receptor-coupled event or by a membrane depolarization (not shown). A rise in the Ca2+ concentration in the domain just beneath the plasma membrane, [Ca2+Isin, can lead to an activation of the Ca2+ pump either via a direct calmodulin (CaM)-dependent mechanism, or indirectly via the activation of protein kinase C (CK). Additionally, in some cells, an increase in cGMP concentration also increases Ca2+ efflux (not shown), and in still others cAMP may stimulate Ca2 efflux.

Fmoc-cleavage (time, % Pip./DMF) Coupling-time (hours)... 

Figure 29-2. Postulated effect of lithium on the IP3 and DAG second messenger system. The schematic diagram shows the synaptic membrane of a neuron in the brain. PLC, phospholipase-C G, coupling protein R. receptor PI, PIP, PIP, IP, IP, intermediates in the production of IP3. By interfering with this cycle, lithium may cause a use-dependent reduction of synaptic transmission. (Modified and reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

A special application of the Japp-Klingemann coupling involves the use of 3-carboxy-2-pip-eridone <56JCS4593>. After couphng, decarboxylation and cyclization, l-oxo-l,2,3,4-tetrahydro-/ -carbolines are obtained. Under acidic conditions these can be hydrolyzed to tryptamines (Scheme 60) <89JOC2170,93SC1689>. 

The line widths are reasonably narrow ( < 150 Hz) except in the case of the mixed ligand species, cis-[Mo(CO)4(pip)(PR3)], for which scalar coupling between the Mo and P nuclei is not easily resolved. Coupling between Mo and N-14 nuclei is not generally observed and is much smaller = 32-45 than /( Mo- P) values. The... 

The second kind of transformations are done for chemical reasons and comprise the called "constant-row sum" and "normalization variable" (Johnson Ehrlich, 2002). Dealing with compositional data, concentrations can vary widely due to dilution away from a source. In the case of contaminated sediment investigations, for example, concentrations may decrease exponentially away from the effluent pip>e. However, if the relative propwrtions of individual analytes remain relatively constant, then we would infer a single source scenario coupled with dilution far away from the source. Thus, a transformation is needed to normalize concentration/ dilution effects. Commonly this is done using a transformation to a fractional ratio or percent, where each concentration value is divided by the total concentration of the sample Row profile or constant row-sum transformation because the sum of analyte concentrations in each sample (across rows) sums unity or 100% ... 

In some cases, the filter is used as both particulate trapping medium and as a substrate for holding a derivatizing reagent that reacts with and stabilizes the particulate matter. For example, l-(2-pyridyl)pip-erazine-coated glass fiber filters are used to trap and react with particulate methylene bisphenyl isocyanate to form a derivative that is then analyzed using HPLC coupled with a fluorescence detector. 

Other methods for this derivahzahon approach include the use of phosphinous acids, such as (EBu)2P(OH) for couplings of aryl chlorides [42] in the presence of tetrabutylammonium bromide (TBAB). Further, ammonium salts of hindered phosphines, such as 2-(di-terfbutylphosphino)ethyltrimethylammonium chloride (FBu-Amphos) or 4-(di-tert-butylphosphino)-N,N-dimethylpiperidinium chloride (FBu-Pip-phos), were employed for efficient couplings of unactivated aryl bromides at mild temperatures [43]. 

Z.-tryptophan, and the subsequent cyclization to form the hexahydropyrroloindole moiety the y-hydroxylation of the pipeiazic acid (Pip) motif catalyzed by HmtN and the biaryl aromatic coupling between cyclic depsipeptide monomers catalyzed by HmtS to create the active dimer form of himastatin... 

Shi recently reported on the Ni(ll)-catalyzed alkynylation of aromatic amides containing a (pyridine-2-yl)isopropylamine (PIP) as the directing group with ethy-nyl bromides as coupling partners (Scheme 12) [35]. When weta-substituted aromatic amides were employed, the alkynylation occurred at the sterically more accessible position. A wide variety of functional group were tolerated. The scope of the reaction with respect to ethynyl bromides was wide. Not only a triisopro-pylsilyl (TIPS) group but also a trimethylsilyl (TMS), alkyl, and aryl-substituted alkynes were applicable to the reaction. The reaction proceeded with a high catalyst turnover number (TON) of up to 196. 

Isotropic pyrolytic carbon exhibits excellent stability under neutron irradiation. This, coupled with its high strength, dense isotropic structure, and impermeability to gases, makes it the material of choice for the coating of nuclear fission particles to contain the fission products.PIP I The coating is produced in a fluidized bed (see Sec. 2.7 above). 

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