Anesthetic compounds

Compounds that Cause Kidney Damage Several drugs and some anesthetic compounds such as methoxyflurane cause kidney damage when present at high doses. Kidney-toxic compounds found in occupational environments include mycotoxins, halogenated hydrocarbons, several metals, and solvents (see Table 5.16). 

Finally, Ebalunode et al. reported a structure-based shape pharmacophore modeling for the discovery of novel anesthetic compounds (88). The 3D structure of apoferritin, a surrogate target for GABAa, was used as the basis for the development of several shape pharmacophore models. They demonstrated that... 

W. (2009) Structure-based shape pharmacophore modeling for the discovery of novel anesthetic compounds. BioorgMed Chem 17, 5133-5138. 

Analgesic efficacy and clinical use Fentanyl (Clotz and Nahata, 1991) is a potent analgesic and anesthetic compound. It is used for the treatment of severe acute and chronic pain, as a pre-medication or adjunct to anesthesia and as a primary anesthetic for the induction or maintenance of anesthesia. In combinations with neuroleptics e.g. droperidole, it induces a pain free and calm state known as neuroleptanalgesia (Foldes, 1973). In this condition, surgery can be performed in an awake patient, who is able to cooperate with the surgeon. 

Aberg, G. Toxicological and local anesthetic effects of optically acitve isomers of two local anesthetic compounds, Acta Pharmacol. Toxicol. 1972, 31, 444-450. 

Airborne toxicants can be simplified to two general types of compounds, namely gases and aerosols. Compounds such as gases, solvents, and vapors are subject to gas laws and are carried easily to alveolar air. Much of our understanding of xenobiotic behavior is with anesthetics. Compounds such as aerosols, particulates, and fumes are not subject to gas laws because they are in particulate form. 

Are there any stereochemical requirements of local anesthetic compounds when they bind to the sodium channel receptors A number of clinically used local anesthetics do contain a chiral center (i.e., bupivacaine, etidocaine, mepivacaine, and prilocaine) (Table 16.2), but in contrast to cholinergic drugs, the effect of optical isomerism on isolated nerve preparations revealed a lack of stereospecificity. In a few cases (e.g., prilocaine, bupivacaine, and etidocaine), however, small differences in the total pharmacological profile of optical isomers have been noted when administered in vivo (41,42,43). Whether these differences result from differences in uptake, distribution, and metabolism or from direct binding to the receptor has not been determined. 

The anesthetic compound halothane, CF3CHBrCl, is metabolized in the liver and this process has been monitored using F NMR spectroscopy, both in vivo and in dissected rat livers. Initially, several resonances were observed in vitro which did not correspond to trifluoroacetate or fluoride, two known metabolic products. Using surface coil NMR experiments in vivo, it has been possible to show that the halothane has a first-order decay in the liver with a half-life of 2.5 h, that trifluoroacetate was observed 8 h after dosing, and that induction of liver enzymes shortened this period considerably. No other resonances were observed in vivo but in liver extracts other molecules were also detected, namely, fluoride, CF3CH2CI, and CHF2CH2CI. 

According to the Meyer-Overton hypothesis [14,15], the anesthetic potency of anesthetic compounds is proportional to their solubilities in a non-polar phase, similar to the interior of the neuronal membrane. The remarkable aceuracy of this relationship for all elinical and many other anesthetics led to its broader interpretation that anes-theties act inside the neuronal membrane [36]. Then, the Meyer-Overton hypothesis implies that the same concentration is required for all anesthetics to exert anesthetic action, irrespective of their molecular structure. Their action may be either nonspecific or directed at selected membrane receptors. 

Once a large database of anesthetic compounds is examined the correlation predicted by the Meyer-Overton relationship is less convincing. In Fig. 9, we show the... 

Fig. 9 Log-log of MAC vs. solubility in A olive oil, B octanol, and C hexane for clinical anesthetics (circles), n-alkanols (triangles), transition compounds (squares) and other anesthetic compounds (diamonds)...

Within the narrow interpretation, our results suggest that solubihties at interfaces between water and a nonpolar liquid allow the prediction of potencies for a broad range of anesthetic compounds better than solubilities in environments that model the interior of the membrane. In a broader view, a very good correlation between MAC and interfacial solubilities suggests that the sites of anesthetic action are located near an interface. A natural candidate site is the head group region of the neuronal membrane. Another possibility is an interface between the aqueous solvent and a hydrophobic patch in a water-exposed portion of a membrane receptor. 

Interfacial activity of small molecules at the interface has several implication of biological and pharmacological importance. For example, interfacial concentrations of a broad range of anesthetic compounds correlate very well with their anesthetic potencies, suggesting that the site of anesthetic action is located near the water-membrane... 

New anesthetic compound - tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c] pyrazole (104) has been prepared by reaction iodopyridine 103 with CsF in DMSO without change of stereochemistry at rather hard conditions (60 min. at 200 °C) [90] (Scheme 40). Compounds 104 are modulators of receptors of cannabinoids and can be used against a cancer and Alzheimer s and Parkinson s diseases [90]. 

Figure 4 Free energies of transferring the anesthetic compounds isoflurane, nitrous oxide, ethanol, hexanol and l-chloro-l,2,2-trifluorocyclobutane across a GMO membrane. The center of the membrane is at 2 = 0 and the water lies to the right.

Anesthetics Many anesthetic compounds inhibit luciferase by competitively binding to the substrate (aldehyde)-binding site. However, the strength of competitive inhibition has a poor correlation with the strength of general anesthetics (14). 

Using a similar strategy, we also envisioned the asymmetric synthesis of another anesthetic compound, "Hoechst s ether (see Scheme 4). This molecule was first synthesized in racemic form by chemists at Hoechst (24), The mixture of four diastereomers was patented as an anesthetic, but its properties were not desirable enough for it to be brought to market. The situation here is more complicated because there are two chiral centers to deal with in an asymmetric synthesis. To keep things manageable, we decided to control the stereochemistry at only one of the chiral centers. The product in this case would be a pair of diastereomers. If we were successful, we hoped that one or both of the diastereomeric pirs would have improved anesthetic properties vs. the racemate. The first big hurdle was a synthesis of the enantioenriched acid, which turned out to be relatively simple (Scheme 7). 

---