Chirality By Dr. Ahmed Mostafa Assist. Prof. of anesthesia & I.C.U Benha faculty of medicine

Chirality  Is a property of asymmetry important in several branches of science.  The word chirality is derived from the Greek, χειρ (kheir), "hand", a familiar chiral object.  An object or a system is chiral if it is not identical to its mirror image, that is, it cannot be superposed onto it.

Chirality  A chiral object and its mirror image are called enantiomorphs (Greek opposite forms) or, when referring to molecules, enantiomers.  A non-chiral object is called achiral and can be superposed on its mirror image.  The term was first used by Lord Kelvin in an address in In a lecture given in Johns Hopkins UniversityLord KelvinJohns Hopkins University

Chirality For example:  Human hands are the most universally recognized example of chirality: The left hand is a non- superimposable mirror image of the right hand; no matter how the two hands are oriented, it is impossible for all the major features of both hands to coincide.

Chirality  Clockwise is different from anti-clockwise.  Spun string.  The J, L, S and Z-shaped.  Gloves, glasses and shoes.  Some chiral three dimensional objects, such as the helix.

Drug chirality  Approximately 56% of drugs currently in use are chiral compounds, and 88% of these chiral synthetic drugs are used therapeutically as racemates.  A chiral center is formed when a carbon or quaternary nitrogen atom is connected to four different atoms. A molecule with one chiral center is then present in one of two possible configurations termed enantiomers.

Drug chirality

-These enantiomers have identical physical and chemical properties, but rotate polarized light in opposite directions. They are commonly referred to as optical isomers and are non- superimposable mirror images of each other. N.B: The light usually used for the determination of optical activity is sodium light; at other wavelengths, the rotation will be different, may be zero, and may even reverse in direction compared with the rotation given with sodium light.

Drug chirality  One of these isomers rotates a beam of plane polarized light in a counterclockwise direction and is defined as the levorotatory or l enantiomer, and the angle of rotation is defined as a negative (–) rotation. The other isomer rotates light in a clockwise direction and is defined as the dextrorotatory or d enantiomer, and the angle of rotation is defined as a positive (+) rotation.

Drug chirality

 The earliest method of distinguishing one enantiomeric form from another was by the sign of rotation, i.e. d and l or (+) and (–) forms. Unfortunately, this did not describe the actual spatial arrangement around the chiral centre, known as the configuration.  Consequently, a convention was developed based on the sequence of substituents around the asymmetric centre.

Drug chirality  Another convention, which largely is historical, is based on the configuration of a molecule in relation to (+) glutaraldehyde, which arbitrarily was assigned a ‘D’ (not ‘d’) configuration. Compounds were denoted ‘D’ or ‘L’ according to comparison with the model substance, and the optical direction added where appropriate. It is recommended that this method of description be limited to stereoisomers of amino acids and carbohydrates.

Drug chirality  The currently accepted convention is that which assigns a sequence of priority to the four atoms or groups attached to the chiral center. The molecule is described as though it were being viewed from the front with the smallest group extending away from the viewer. If the arrangement of the largest to the smallest groups is clockwise, then the enantiomer is designated ‘R’ for rectus. If the arrangement is anticlockwise it is designated ‘S’ for sinister. The optical direction is then added to complete the description.

Drug chirality Lactic acid, an asymmetric molecule, and its mirror image.

Drug chirality

 The separation of enantiomers has an interesting background. In 1848 Louis Pasteur, using a hand lens and a pair of tweezers, painstakingly separated a quantity of the sodium ammonium salt of paratartaric acid into two sets of enantiomeric crystals. Because paratartaric acid (also known as racemic acid) was the first compound to be resolved into optical isomers (enantiomers), an equimolar mixture of two enantiomers is now called a racemate.

Drug chirality  Most of the synthetic chiral drugs used in anaesthesia are administered as racemic mixtures (for example, the inhalation anesthetics, local anesthetics, ketamine), although some are single, pure enantiomers. Halothane, enflurane and isoflurane contain a chiral center and can exist as R and S isomers.

Drug chirality  Although the mechanism of anesthetic action is not yet clearly understood, it has been shown that the pure enantiomers of chiral inhalation anesthetic agents interact differentially with the CNS ion channels.  Many naturally occurring compounds (formed by organisms or derived from plants) contain one or more chiral centers; however, their synthesis is usually stereo-selective so that specific isomers are formed (e.g. d-tubocurarine, l-hyoscine and l-morphine), which are used therapeutically.

Drug chirality  An exception is atropine which occurs naturally as an l-isomer but is partly converted to its enantiomer during extraction and is consequently given as a racemate (dl- hyoscyamine). Since d-hyoscyamine has very little anticholinergic activity, the overall effectiveness of atropine is significantly reduced.

Drug chirality  Today it is well recognized that changes in the enantiomeric makeup of chiral drugs may very significantly alter their pharmacokinetic properties and pharmacological and toxicological profiles. Past practice was to develop racemates as drugs, either because their separation was difficult from a commercial perspective or the properties of the individual enantiomers had not been properly investigated.

Atracurium Is a complex mixture of 10 stereoisomers and is usually administered as the chiral mixture. Among these, cis-atracurium was isolated and its pharmacological properties were examined. This isomer offers clinical advantages over the mixture, principally due to the lack of histamine- releasing propensity and the higher neuromuscular blocking potency.

Dobutamine Dobutamine is a racemate of two enantiomers both of which are positive inotropes. R (+)- dobutamine acts on β1 and β2 receptors, whilst S (–)-dobutamine acts on α1 adrenoreceptors. Since both isomers have similar desirable activities, this is an example where it is preferable to administer the chiral mixture rather than a single enantiomer.

Ketamine

The S (+) isomer of ketamine has: -Twice the analgesic potency. -Three times as potent as the R (–) isomer. -The recovery phase was found to be shorter after S (+)-ketamine, compared with the racemate. -Less incidence of psychotic emergence reactions.

Bupivacaine S (–) bupivacaine has: -longer duration of action. -Less cardiovascular toxicity. -Some vasoconstrictor activity.

Prilocaine  The S(-)enantiomer is: - Stronger vasoconstrictor. -Metabolised more slowly than the R(+)-form. -Less risk of methaemoglobinaemia.

Ropivacaine  This is the pure S(-)enantiomer of propivacaine.  Is associated with a safer cardiovascular profile in overdose. N.B: Lignocaine is achiral.

Tramadol The R (+) enantiomer appears to have: -Relatively low activity at µ- receptors. -Higher affinity of its main M1 metabolite results in a six fold increase in analgesic potency. The S (-) enantiomer acts to inhibit the re- uptake of noradrenaline and 5-HT within the CNS.

Labetalol The mixed adreno-receptor blocker, is commercially available as equal proportions of four stereoisomers. Nonspecific β1- and β2- blocking activity is mainly conferred by the R, R isomer, while α1-blocking activity is produced by the S, R isomer.

Drug chirality  Some enantiomers have different therapeutic activities and as such may be marketed separately. For example, 2S, 3R-(+) dextropropoxyphene is an analgesic, and its enantiomer (–)-levopropoxyphene is an antitussive.  The enantiomeric nature of these two drugs is also reflected in their US trade names, the former being marketed under the name Darvon and the latter Novrad.

Drug chirality  The separation of convulsant and anesthetic activities occurs between the isomers of N- methyl-5- propyl barbiturate, with the S-(+) enantiomers being pure convulsants whilst the R-(–) enantiomers are anesthetics.

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