Functional Surrogates

The refined 4 A resolution electron microscopy structure of the hetero-pentameric musde-type, (al)2jSyd uAChR has elegantly illustrated considerable structural similarity of L-AChBP with the nAChR ligand-binding domain. Therefore, L-AChBP is now considered a structural and functional surrogate of the nAChRs. 

Urea Pharmacokinetics. Pharmacokinetics summarizes the relationships between solute generation, solute removal, and concentration in a patient s blood stream. In the context of hemodialysis, this analysis is most readily appHed to urea, which has, as a consequence, become a surrogate for other uremic toxins in the quantitation of therapy and in attempts to describe its adequacy. In the simplest case, a patient is assumed to have no residual renal function. Urea is generated from the breakdown of dietary protein, accumulates in a single pool equivalent to the patient s fluid volume, and is removed uniformly from that pool during hemodialysis. A mass balance around the patient yields the following differential equation ... 

The drugs in this class share the phenyl ethanol amine moiety and a catechol surrogate in which the 3-hydroxyl is replaced by some other function that contains relatively acidic protons. 

BENZENESULFONIC ACID DERIVATIVES As has been discussed previously, substituted -alkylbenzene-sulfonylureas often possess the property of releasing bound insulin, thus sparing the requirement for insulin injections in adult-onset diabetes. A pyrimidine moiety, interestingly, can serve as a surrogate for the urea function. 

At typical indoor concentrations, COj is not thought to be a direct cause of adverse health effects however, COj is an easily-measured surrogate for other occupant-generated pollutants. Eye, nose, and throat irritation headaches lung cancer may contribute to heart disease buildup of fluid in the middle ear increased severity and frequency of asthma episodes decreased lung function. ETS is also a source of odor and irritation complaints. 

With the advent of molecular biology and the ability to express transfected genes (through transfection with cDNA) into surrogate cells to create functional recombinant systems has come a revolution in pharmacology. 

It was anticipated all along that the vinylsilane residue could serve as a vinyl iodide surrogate. After protection of the C-14 secondary hydroxyl in 180 in the form of a triisopropylsilyl ether, the vinyltrimethylsilyl function can indeed be converted to the requisite vinyl iodide with AModosuccinimide (NIS) (see 180—>181, Scheme 43). Vinyl iodide 181 is produced stereospecifically with retention of the A17,18 double bond geometry. This transformation is stereospecific since the stereochemistry of the starting vinylsilane and the vinyl iodide product bear a definite relationship to each other.67b 75... 

The presence of particles in the brains of experimental rats and humans exposed to asbestos has been reported (Pontefiart and Cunningham, 1973 Auerbach et al., 1980). In experimental studies, particles of Teflon, a reflux paste, enter the brain via intravascular transport when injected into the bladder (Aaronson et al., 1993). Encephalitic reactions to accumulated calcium oxalate crystals in the brain as a result of infusions of glucose surrogate polyol solutions have been described (PciflPcr etal., 1984). Such studies indicate the capacity of particulates to enter the brain and thus pose a potential pathological threat to the functioning of the central nervous system (CNS). 

ACh was first proposed as a mediator of cellular function by Hunt in 1907, and in 1914 Dale [2] pointed out that its action closely mimicked the response of parasympathetic nerve stimulation (see Ch. 10). Loewi, in 1921, provided clear evidence for ACh release by nerve stimulation. Separate receptors that explained the variety of actions of ACh became apparent in Dale s early experiments [2]. The nicotinic ACh receptor was the first transmitter receptor to be purified and to have its primary structure determined [3, 4]. The primary structures of most subtypes of both nicotinic and muscarinic receptors, the cholinesterases (ChE), choline acetyltransferase (ChAT), the choline and ACh transporters have been ascertained. Three-dimensional structures for several of these proteins or surrogates within the same protein family are also known. 

The C-H functionalization protocol is not limited to the development of surrogate chemistry to enolate transformations. The C-H activation at allylic C-H bonds readily generates 7,6-unsaturated esters, the products of the classic Claisen rearrangement (Figure 6). 

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