—_— SPECIAL ARTICLE Paver 4 Weak Intermolecular Associations and Anesthesia came Sandor, Po. THE righ sructure and functioning of biologic macro: ‘molecules are ensured by a great umber of intermolee lar associations, hydrogen bonds, and yan der Waals associations Because general anesthesia must be revere ble its action i likely to consist in the replacement or perturbation of weak hydrogen bonds or van der Waals sociations by others involving the anesthetic. A qual: lative understanding of general anesthest can be based fn this idea "Hydrogen bonds (H-bonds) are ubiquitous in natre. Ke ‘sno overstatement to say that fe would not be posble -wathout them. Water would ot be liquid at ambient temperature; water, proteins, mle ads, and sacchs. fides that are the main constituents of living bodies ‘would noc have their specie steucures that enable them co full their functions. Nature wes Hbonds whenever a certain degree of sable needed as well sversty. Al his eatiraly applies tothe constituents of the nervous system. Moreover, as anesthesia repre- Seats a interference withthe normal functioning ofthe nervous system, it would be surprising i Heads were fot involved withthe mechanism of anesthesia, THis does aot mean, however, that other types ofintermolce- lar asocations sre not involved. ‘This iew took ato time to become widespread. The fact that general anesthedies are usually lipid a not water soluble and that there i 4 correlation between, lipid sotubitty and anesthetic potency (the Meyer Over- ton rule focused the attention of researchers on nom po larinteracions in the hydrophobic parts ofthe lip cell membrane and, later, of proceins,Fxcellent rica re- views on this evolution ate avaiable ™* “The most important tact foe the present discussion tha general anesthesia occurs through a interplay of Intermolecular interactions withort proper chemical re: actions, although cersin anesthetics metabolize afer ‘exerting their action. So the question is thi: what kind of termoceular interactions ae involved? Ac tis point fone mast remember the extreme variety ofthe chemical Steucture of anesthesies, Neat all molecules have some anesthesc potency. Among these afe rare iss, sat ‘ted hydrocarbons, alcohols, ethers, ketones, and halo: gure hl piano ebm Oster ep ‘Ree aut sper ero oy Som eins are Aerts, V 101 Ne 5, No 2004 czrbons, among others. A chemist could hardly admit ‘hat they all exert their action by the seme “unary” ‘mechanism. The differences shouldbe looked fori the nature of intermolecular aceractions that ae imvoive. A pluralistic theory was peoposed.*? Present research teads to locate the site of action of anesthetics in the neurotransmitter receptors a the si apse.” The seceptors are proteins, polly gycopre teins or lectins." The strucire of these macromolectles and their conformations that are adapted to thei Ane ions are ensured by a great numberof itermolecuae Interactions, van der Waals or H-bonding, Some anestbet lcs ike Xenoae ean he sipposed to ke only an der ‘Waals interactions where the main fictor is polaiabil ‘ay. However, most of them possess atoms or grou that ‘an act as proton donors of acceptors, or both. Thi ie ‘hy the role of F-boading seems tobe inevitable 'A typical example are the widely wed anesthetles ‘which are halocarbons containing the “aide hydrogen” like chiorofom, halothane, methoxyfran, isourane, enflrane, and others!" Such molecules can form H- bonds as weak proton donors. Evidence has been pro vided by intrared specroscopic methods that these ‘weak Hboads can alter significantly the free/Atbonded. equilibrium even in much stronger Tbonds of the (OF. 20 or NHL. types "*"* The reasons for this ‘ere investigated by quantum chemical thermodyaamic Calculations ""*" 4 corretaton was found between the bond bond breaking ability of cklc hydrogen contain {ng halocsebons and thee anesthetic potency. ‘he idea thatthe formation and perushation of Ht bonds pays ale the mechanism of general anesthe sia was advocated ina series of publications from the author's laboratory." More recently Brockerhofl ef ‘a and Abraham ea” assessed the ole of Hhonding {the mechanism of general anesthesia. ‘Then the next question 5 this: what type of Htbonds are likely to be affeced by anesthetics? There exists & reat variety of Hebonds; ther energy enthalpy) varies fom <1 to approximately 50 keal/M. From the point of view ofthe living organism the Weaker ones are the mast Important Anesthetic action must, of course, be revere Ible, so the perturbation that fen mst fll into the range of thermal fluctuations or other weak—van der Waals—interactions. Because weak Hbonds are long range Interactions fling off with ©", chey are stil sg rieant at H.--X distances of 3.0 or 3.5 A" They have fenergles (enthalpies) on the order of I or 2 kes/M, Teleey and Saenger devote a chapter to weak H-bond lng interactions in biologie systems: “Weal Hydrogen Bonding Interactions Formed by CHT Groups ax Donors 12s,1236 and Aromatic Rings as Acceptors** These ar, indeed, among the THbonds most eligible o play a role in the ‘mechanism of mnesthesa™ Desi and Steiner more ccently devoted their book to weak H-bonds” They sve thorough consideration to CH... and CH, .N fmteracions, #7 and other weak H-bonds, Aa i smease variety of al these exists Inthe living organisa, Such bonds are expected to be reverb pereuthed by all kinds of anesthetic molecules. “Thorton eta. Skigh and Thorton and Michell et aL obtained ienportant resus on amlno/aremate in- teractions ia proteins. They did find amino/aromatic bonds but also, more frequently, stacked ing suc tures. This they explained by the "potential of structures for extra conventional hydrogen bonding o either pro- fein or solvent." The enesgy in stacked sructures s of clectrosttic origin with some 2 = overlap according {o eases: could also be perturbed by anesthetics, Gur shy ef a2 studied stereospecific dhaloallane binding in Insulin crystals and concluded that both dispersion snd polar interactions must contabute signiicandy to the binding enthalpy and stereospecific Burley and Peisko"™ studied aromaticaromatic and aminoaromatic imericuons as 2 mechanisa of protein stmucture stabilization. Berger and Eg examined the role of GH, ..0 Hibonds. Atwood etal provided Xeay Aeacion evidence for aromatic = H-bonding to water ‘Klessting et al* poinced out that aromatic amino acid side chains interact with bound sugary in numerous structures. Weis and Drickamer® noted that aliphatic protons of dhe sugar ring beara small paral postive charge that could lead to weak interactions with the ‘cloud of aromatic resucs, Proteincrbohydrate ree: Ognition isan important mechanism in physiologic fee ‘gnition processes. The many hydroxy groups in eano- hydrates can form Hbonds with amino acid residues, Some ofthese interactions are mediated by water mole- cules A very great umber of such weak bonds ensure the right stractureof biologie macromolecules, The x0- thor made the propos” thar oligosaccharides assoc sed with proteins could be targets for anestheties both A theisbyaophobie rings and at thee OH groups. ‘elssignicant hat neurotransmiters ll contain OH oF INH groups prone to form H-bonds. On the other hand, neurotransmitter receptor aloo contain numerous ‘soups that are proton donors or acceptors Recently Eckenhf «fal examined the binding of volatile anesthedes to proteins by using a number of techniques, ia purticula he tuorescence of tryptophan ‘Volatile anesthetics bind wo proteins at cavities in pro imity to tryptophan residues. Even if the distance approximately 104 the bond could be mediated by water molecules, “Johansson ef al provided experimental sipport to the effec that small anesthetic aalecules ean bind in cities formeat erween mhclces, They examined the ‘SANDOAFY structural requirement for an inhalational anesthetic binding se on a protein target andthe way in which they alter proce nti in the centr nervous system, All this does noc mean that KFbonds are the ony weak associations that are involved with the mechanism of seneral anesthesia Hydrophobic, van der Waal interae- tions are also important determining the right confor mations of biologie macromolecules. Rare gases O ft rated hydrocarbons can be expected to affect mainly these. Alcohols were shown t© act at the waterlipid Interface of the nerve cell membranes.” However, many anesthetics are amphiphise and could afece both H- bonds and van der Waals associations. Halothane, in particular, hs a bromine atom that can undergo assoc ations. To a lesser extent this can alo be ssid about ‘Chlorine atoms. Ie could be shown, however that this tendency i weaker than the tendency to H-bond forma tion. The mechanism is expected to consist in the scversble replacement of perturbation of weak existing Webonds or van der Waals associations by other weak Hibonds or van der Waals asociatios involving the anesthetic. This would explain the reversibility of gen eral anesthesia as well asthe great variety of moleces Inrving anesthetic potency. ‘Whether the anesthede severs an existing Hbond or only induces changes ia is geometry tance, angle) ‘could depend on eases. A retavely sight pertrbation ‘ould be enough to induce conformational changes in proteins. The perturbation might affect Hhonds or van Ina recent article on molecular modeling of anesthetic fneractions, Trdell and eraccia pointed ont that the nicotinic acetylcholine receptor requtes cholesterol {or proper fonctioning. Jones and McNamee, *” Corbin et a Rankin et al, and Mercier ef al stated the ‘elation between the slfassoctation of cholesterol and lis association with ester and amide groupe, as well as the extent «0 which acidie hydrogen containing anes: theles can interfere with these, Cholesterol as 20 oaly 1 large hydrophobic core but ako an OH group that i highly astocatve. Among the possible Htonds there fe ‘one tht i quite weak, the estercholesterl O_O = € bond. tt could be an easy target that anesthctics could pereurb reverb. This seems to bes another post. Conclusions All this requires experimental support. It appears, however, tht the following points can be made Weak bonds and yan der Waals contacts contribute to cnsire the right conformation of proteins Thercore severing for perturbing such iatesetions ould induce conform: tional changes in proteins that in tim, could cause anesthesia. Anesthetics are likely to perch several of these to exer thee action. Both polar and nonpolarWEAK ASSOCIATIONS AND ANESTHESIA Interactions can be important. Different anesthetics sight affect eiferent weak interactions in accordance ‘With their own chemical sructure. The action of every anesthetic, neurotransmitter, and receptor needs special Consideration: wnitry” views should not be imposed References “em en che in gd ete immer asa mete Sen ‘Set Fay Cn on Rew cg iRoge DM. 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