QSAR Studies on the Anesthetic Action of Some Polyhalogenated Ethers Ahmad R. Mehdipour 1 , Bahram Hemmateenejad 1,2 * and Ramin Miri 1 1 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, 71345-1149 Shiraz, Iran 2 Department of Chemistry, Shiraz University, 71454 Shiraz, Iran *Corresponding author: Bahram Hemmateenejad, hemmatb@sums.ac.ir There has been an on-going debate about the mode of action of general anesthetics and until now, many sites have been postulated as target site for action of these compounds. Here, some quantum chemical-based quantitative structure- activity relationship (QSAR) models were devel- oped for a set of polyhalogenated ethers in order to investigate the aspects of their anesthetic action, which is not completely defined yet, although some hypotheses have been suggested. A data set including 25 polyhalogenated methyl ethyl ethers were selected, and different descrip- tors were calculated for each molecule using density functional theory calculations, and subse- quently some multilinear QSAR models were built by using different sets of the calculated molecular descriptors. The result showed that polar (polariz- ability) and non-polar (log P) parameters have mixed role on the anesthetic activity i.e. models with high statistical quality were obtained in com- bination with these two parameters. Also a good model between anesthetic action and electrostatic potentials was obtained, which may imply the important role of electronic interactions in the anesthetic activity of the compounds. Finally, a four-parametric QSAR model containing log P, molecular polarizability, most positive charge and an electrostatic potential parameters was obtained, which indicated that the anesthetic action of the polyhaloganted ethers may be pro- ceeded through lipophilic, steric and columbic interactions. Key words: general anesthetics, polarizability, quantitative struc- ture-activity relationship, quantum chemical Received 5 February 2007, revised 5 April 2007 and accepted for publi- cation 11 April 2007 Quantitative structure-activity relationship (QSAR) models mostly have two distinctive abilities: prediction and description. These two properties are separated from each other and may have different rank, i.e. some models may be more predictive or vice versa. Des- criptive models mostly used for explanation of a chemical or biolo- gical process (for instance, mechanism of action of some drugs). In this manner, models get some chemically meaningful descriptors, which can explain some aspects of mechanism of drugs or chemi- cals in human or animal body (1–4). General anesthetics are a class of drugs, which are used for per- forming surgical intervention in the absence of consciousness. At the turn of the 20th century, Meyer and Overton separately sugges- ted a theory about anesthetic activity that lipophilicity is directly related to the potency of the substance used as an anesthetic (5,6). They stated this in a simple equation: some measure of lipophilicity in olive oil/water partition coefficient time to some measure of anesthetic potency equals to a constant (7–10). These observations led them to this theory that general anesthetics act non-specifically on hydrophobic component of neuronal membrane cells (8). This theory has been the unique theory for explanation of general anes- thetics mechanism of action for nearly half a century. However, from 1960, data opposing the lipid theory began to accumulate. Frank and Lieb proposed that general anesthetics act directly on proteins (7); at nearly the same time, the first X-ray structure of an anesthetic, halothane, bound to a specific site in adenylate kinase appeared (11). On the contrary, some compounds were deviated from Meyer–Overton equation; they showed lower or higher activity predicted by equation. In addition, some volatile anesthetics inclu- ding isoflurane, desflurane and enflurane are containing an asym- metric carbon; thus they can exist as (+) or ()) enantiomer. It has been indicated that (+)-Isoflurane is about 50%–60% more potent than its enantiomer (12). These finding argue against Meyer–Over- ton theory and suggest the need for more complex mechanism. Until now, many sites have been postulated as target site for action of general anesthetics. More recently, investigators have determined the effect of anesthetics on a number of protein receptors (10) such as GABA (13–15) and NMDA (15) and also ion channels, including potassium, and chloride channel (16–22). In this period, parallel to experimental efforts, many groups tried to model the relationship between properties and activity. As general anesthetics are not sharing a common three-dimensional structure feature, some investigators have sought for correlation between potency and physicochemical properties such as lipid solubility (23), partition coefficient, molar refraction and boiling point (24). However, others tried to model some QSAR or even 3D-QSAR 362 Chem Biol Drug Des 2007; 69: 362–368 Research Article ª 2007 The Authors Journal compilation ª 2007 Blackwell Munksgaard doi: 10.1111/j.1747-0285.2007.00506.x