Review Article ISSN 2277-3657 Available online at www.ijpras.com

International Journal of Volume 1, issue 4 (2012),7-10 Pharmaceutical Research & Allied Sciences

Chiral in Pharmacology – A Review Dr M Kiran 1, Dr P Yadav 2, Dr P Deolekar,3 Dr V. Thakre 4 1Resident in pharmacology, 2Associate professor in Pharmacology, 3Lecturer in Pharmacology, 4Assistant lecturer in Pharmacology Dr. D. Y. Patil Medical College, Navi Mumbai Corresponding address: [email protected]

Subject: Pharmacology Abstract is a branch of Chemistry involving the study of relative spatial arrangement of within the . Stereoisomers of a same pharmacological agent may show different pharmacological activity on different receptors and on different systems. They are classified as Constitutional Isomers and Stereoisomers. also influences a lot of Pharmacological Processes ie at both pharmacodynamic level, safety level and also at pharmacokinetic levels. One of the most important advantages of studying Chirality in Pharmacology is removal of unwanted adverse effects, if due to an isomer. Newer interest has developed in studying isomers of already existing drugs as individual drugs, in a quest to find a drug which is highly safe and efficacious as well.

Keywords: Chiral Chemistry, Stereochemistry, Chirality, Isomers, pharmacology

Introduction and History: Stereochemistry is a branch of Chemistry involving stereochemistry. In 1898, Lord Kelvin designed the the study of relative spatial arrangement of atoms first model of actual measurement of Chirality with within the molecules. Chirality is the property of the help of microwave radiations. This first model certain molecules to have the same molecular has acted as a development tool form many formula but different . Isomers are sophisticated instrument in stereochemistry for molecules with same molecular formula but different measuring and changing the Chirality of a . 2 structural formula. Racemicity is a word derived from the word racemes, which means bunch of grapes. So Importance to Pharmacology: it is the mix of all the possible with that Drugs are chemical entities so the property particular compound. 1 of Chirality is also applicable to drugs. Many isomers In 1815, a chemist Jon Baptiste Biot first of a single drug are possible but the real question is thought and postulated the theory of Chirality. Louis that whether these isomers are chemically stable? But Pasteur who is also known as the father of modern there are certain pharmacological agents who do medicine first observed the phenomenon of Chirality show the property of Chirality and the isomers of in 1848. He observed that which is the such agents are chemically stable. These by product of the wine industry derived from stereoisomers of a same pharmacological agent may different types of grapes was able to rotate the plane show different pharmacological activity on different of light differently. Tartaric acid derived from certain receptors and on different systems. For example D variety of grapes used to rotate the plane of light to isomer of has got more activity in the right whereas some to the entirely opposite direction. CNS where it causes stimulation. L isomer of Jacob Henricus Van Hoff first defined Chirality and Amphetamine is CVS specific, where it causes isomerism in 1873. Because of his contribution to increase in the systolic and diastolic BP. 3 this field, he is also called as the father of 7

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Rules of Chirality applicable to Pharmacology: These are not mirror images of each other and are not Pfeiffer Rule : 4 Sir C.C. Pfeiffer first observed that if super imposable. a correct isomer is used instead of a , They are further sub classified into 2 types. then reduction in dose is possible. This is better 1) Configurational Isomers also known as Cis- trans explained with 2 examples isomers. a) the dose required of d – Amphetamine to 2) Conformational Isomers. treat attention deficit hyperactivity disorder (ADHD) is much less than the racemic Amphetamine. Cis - Trans Isomerism or Configurational b) Rabeprazole a proton pump inhibitor has isomerism 5 two isomers, d and l. only d – Rabeprazole has got activity at the proton pumps. The l isomer is inert. So In this isomerism the functional groups if on one side if we use d – rabeprazole (dexrabeprazole) the dose or the same side then they are called as Cis or same require will be lesser than racemic Rabeprazole. side isomer.When the functional groups are on the opposite side they are called as trans or opposite side Cahn Ingold Prelog Rule (CIP rule ):5 isomers.Eg : cis – platin or is a This rule explains the role of chiral centre which is antineoplastic chemotherapeutic agent, but trans – also called as the stereocentre. Chiral centre is the platin is inert. area of the chiral molecule which retains its position in all the possible isomers of that molecule. Confirmational isomerism 5 For pharmacological agents there are many Here the rostation of a group is seen with respect to chiral centres which are present. So many isomers are chiral centre. possible. It differs from Cis trans isomerism by lacking Number of isomers α Number of chiral centres substitution. present in the compound But chemical stabitities of such isomers is a question. They are of 2 types:- Conformers and Rotamers Classification: 6 The only difference between them is conformers are 1. Constitutional Isomers seen for aliphatic compounds whereas rotamers are 2. Stereoisomers for cylical aromatic compounds 3. (geometric isomers) Examples: various amino acids have conformers and 4. Configuration isomers (cis – trans isomers) rotamers 5. Conformational isomers 6. Conformers : 6 7. Rotamers This is the most important type of isomerism. As 8. Enantiomers (optical isomers) many pharmacological agents show this type of 9. D/L System of nomenclature isomerim. 10. R/S System of nomenclature In chemistry this type of isomerism is very popular as it is chemically very stable. Enantiomers are isomers mirror images of each other. Constitutional isomers : 6 They are superimposable. Enantiomers are also called These isomers differ in the arrangement of single as optical isomers as they demonstrate optical in molecule. activity. There are two ways of classifying For example: Practolol a beta blocker is a Enantiomers: Constitutional isomers of Atenolol has been withdrawn from the market due to its eye toxicity. D/L system of Nomenclature : But Atenolol is still used commonly. According to this system the isomers which rotate the plane of light to the right are called as dextrorotatory Stereoisomers: 6 (+) and the ones which rotate it to the left are called These isomers differ in arrangement of entire group as levorotatory (-). Examples: d – Amphetamine and l in a molecule across the chiral centre. – Amphetamine are isomers of Amphetamine. R/S system of Nomenclature: They are of 2 types. This system of nomenclature is independent of the optical activity of the chemical or drug. This system Diasteriomers or Geometric isomers : 6 depends on attachment of the to the chiral centre. The compound which has got the 8

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functional group attached to the right side of the Chirality can influence plasma protein binding as chiral centre is the R isomer (rectus). The isomer well. where the functional group is attached to the left of Example: S isomer of warfarin is bound to the plasma the chiral centre is the S isomer (sinister). Examples : proteins 3-5 times more than the R isomer. Esomeprazole is the S isomer of Omeprazole, Biotransformation 10 Escitalopram is the S isomer of Citalopram. Chirality can influence metabolism of drug as well. Example: R isomer of Methadone is metabolized by Influence of Chirality on Pharmacological CYP3A4 where as the S isomer by CYP2D6. Processes: Elimination 12 • Pharmacodynamic Processes : Half life of isomers can be different than the racemic Efficacy of the drug: 7 mixture. The drug receptor interaction can be influenced by Example : half life of d-Amphetamine is more than l- Chirality. This can be better explained on the basis of Amphetamine. the lock and key model for drug - receptor interaction. Advantages of studying Chirality in Pharmacology: • Removal of unwanted adverse effects, if due to an isomer. • Exposing patient to lower doses of drug with the same therapeutic effect. • Easier assessment of pathophysiology of the disease and reduction in drug interactions. Fig. 1 Drug receptor action • Prevention of isomer-isomer interactions as well. • Avoids possibility of bioinversion. The figure shows that the drug attachment to the • Pharmaceutical Considerations of Chiral Drugs : receptor. But the isomer of the same drug will not be able to attach to the receptor. Thus the isomer will be Analysis of Drug Chirality : 13, 14, 15 lacking the affinity as wellas the intrinsic activity for The methods used are such receptor. 1. HPLC Example: Dexrabeprazole has the activity at the 2. LC-MS proton pumps whereas the l isomer of Rabeprazole is 3. Chiral salt rresolution inert. 4. Chiral CE study • Safety of the drug : 8 5. Changing Drug Chirality : 17, 18, 19, 20 One isomer may be responsible for adverse effects. 6. The methods used are The other isomer may be safe to use in such case. 7. X – Ray crystallography Example : Thalidomide, a drug used for motion 8. NMR Method sickness in late 1950’s caused teratogenic effect on 9. Vibration Circular Dichroism technique the offsprings (Phocomelia). It was later found 10. Chiral zone electrophoresis through animal studies that only the S isomer crossed the blood-placental barrier and was responsible for Summary and Conclusion: teratogenicity. Nearly 60% of the drugs used clinically are chiral • Pharmacokinetic Processes : compounds 21 . But only few of them have been Absorption 9 studied as different isomers, as most of these drugs Biotransport of the drug is affected by Chirality. are studied as racemates. Newer interest has Carrier mediated transport of the drugs across the developed in studying isomers of already existing biological membrane is affected the most. drugs as individual drugs, in a quest to find a drug Example: S isomer of Hexobarbital shows better which is highly safe and efficacious as well. plasma levels as the R form. Distribution 10 Cite this article” Chirality affects distribution as well M Kiran, P Yadav, P Deolekar, V. Thakre “Chiral Example: levodopa is the levo isomer of des oxy Chemistry in Pharmacology – A Review” Int. J. of phenyl or dopa. Levodopa penetrates the Pharm. Res. & All. Sci.2012; Volume 1, Issue 4,7-10 blood brain barrier but the dextro isomer of dopa does not. 9

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