Assignment on ‗Application of isomerism in drug molecules‘

Course – Medicinal Chemistry 2

Submitted by, Submitted to,

Md. Azamu Shahiullah Prottoy Dr. S. M. Raquibul Hasan

Id – 11146018 Lecturer

BRAC University BRAC university

Isomerism

Isomerism, the existence of molecules that have the same numbers of the same kinds of atoms (and hence the

same formula) but differ in chemical and physical properties. The roots of the word isomer are Greek—

isosplus meros, or ―equal parts.‖ Stated colloquially, isomers are chemical compounds that have the same parts

but are nonetheless not the same.

Types of Isomerism

Drug Isomerism and Chirality

Stereoisomers differ in pharmacokinetic and pharmacodynamic properties. Pharmacokinetic differences

resulting out of stereoisomerism can be in Absorption like

L-Methotrexate is better absorbed than D-Methotrexate.

Esomeprazole is more bioavailable than racemic omeprazole

In distribution like S-Warfarin is more extensively bound to albumin than R-Warfarin, hence it has

lower volume of distribution. In metabolism like S-Warfarin is more potent and metabolized by ring

oxidation while R-Warfarin is less potent and metabolized by side chain reduction, half life of S-

Warfarin is 32 hours while it is 54 hours for R-Warfarin.

Levocetrizine has smaller volume of distribution than its dextroisomer.

d-Propranolol is more extensively bound to proteins than l-Propranolol.

Pharmacodynamic differences resulting out of stereoisomerism can be in Pharmacological activity and

potency like

l-Propranolol has beta-adrenoceptors blocking action while d-propranolol is inactive.

Carvedilol is a racemic mixture, the S(-) isomer is a nonselective beta-adrenoceptor blocker, while

both S(-) and R(+) isomers have approximately equally alpha-blocking potency.

S-Timolol is more potent alpha-blocker than R-timolol but both are equipotent ocular hypotensive

agents.

Labetalol is formulated as a racemic mixture of four isomers.

Two of these isomers - the (S, S)- and (R, S)- isomer are relatively inactive, a third (S, R)- is a

potent alpha-blocker and the fourth one (R, R)- is a potent beta-blocker.

Labetalol has a 3:1 ratio of beta: Alpha antagonism after oral administration.

Sotalol is formulated as a racemic mixture of D- and L-isomers, L-isomer has beta-blocking activity

while D-isomer has no beta-blocking activity. The action potential prolonging potential is due to L-

isomer.

Nebivolol has highly selectively beta-1-blocking effects, while the L-isomers causes vasodilatation.

Most beta-2-selective agonist drugs are formulated as a racemic mixture of R- and S- isomers. Only the

R-isomer has the beta-2-agonistic activity while S-isomer has no beta-2-agonistic activity, even S-

isomer promotes the inflammation.

Now a days, Salbutamol is available as a single isomeric preparation of R-isomer as levalbuterol.

Halothane, enflurane, and isoflurane are chiral drugs with different anesthetic potencies. D- (+) 2R,3S

propoxyphene is analgesic while (-) 2S,3R propoxyphene has antitussive action.

Ibuprofen is a racemic mixture. S-ibuprofen is active form and R-ibuprofen is inactive. Dexibuprofen,

its active enantiomer, is marketed now as single enantiomer with an effective dose of 50% of ibuprofen

and fewer side effects.

Ibuprofen containing both (S) and (R) isomers, where it is the (S) isomer that is the eutomer, but the (R)

isomer can bechanged in the body to the (S) isomer. This change from (R) enantiomer to (S) through a

metabolic inversion of configuration does nothing to the (S) but amazingly makes the (R) enantiomer

medicinal like the (S).

Enantiopure Drugs

An enantiopure drug is a pharmaceutical that is available in one specific enantiomeric form. Most biological

molecules (proteins, sugars, etc.) are present in only one of many chiral forms, so different enantiomers of a

chiral drug molecule bind differently (or not at all) to target receptors. One enantiomer of a drug may have a

desired beneficial effect while the other may cause serious and undesired side effects, or sometimes even

beneficial but entirely different effects. Advances in industrial chemical processes have made it economical for

pharmaceutical manufacturers to take drugs that were originally marketed as a racemic mixture and market the

individual enantiomers, either by specifically manufacturing the desired enantiomer or by resolving

a racemic mixture. On a case-by-case basis, the U.S. Food and Drug Administration (FDA) has allowed single

enantiomers of certain drugs to be marketed under a different name than the racemic mixture. Also case-by-

case, the United States Patent Office has granted patents for single enantiomers of certain drugs. The

regulatory review for marketing approval (safety and efficacy) and for patenting (proprietary rights) is

independent, and differs country by country.

The following table lists pharmaceuticals that have been available in both racemic and single-

enantiomer form.

Racemic mixture Single-enantiomer

Amphetamine (Benzedrine) Dextroamphetamine (Dexedrine)

Bupivacaine (Marcain) Levobupivacaine (Chirocaine)

Cetirizine (Zyrtec / Reactine) Levocetirizine (Xyzal)

Citalopram (Celexa / Cipramil) Escitalopram (Lexapro / Cipralex)

Ibuprofen (Advil / Motrin) Dexibuprofen (Seractil)

Methylphenidate (Ritalin) Dexmethylphenidate (Focalin)

Milnacipran (Ixel / Savella) Levomilnacipran (Fetzima)

Modafinil (Provigil) Armodafinil (Nuvigil)

Ofloxacin (Floxin) Levofloxacin (Levaquin)

Omeprazole (Prilosec) Esomeprazole (Nexium)

Salbutamol (Ventolin) Levalbuterol (Xopenex)

Zopiclone (Imovane) Eszopiclone (Lunesta)

The following are cases where the individual enantiomers have markedly different effects:

Thalidomide: Thalidomide is racemic. One enantiomer is effective against morning sickness, whereas

the other isteratogenic. However, the enantiomers are converted into each other in vivo.[3]

Dosing with a

single-enantiomer form of the drug will still lead to both the D and L isomers eventually being present

in the patient's serum and thus would not prevent adverse effects (though it might reduce them if the

rate of in vivo conversion can be slowed).

Ethambutol: Whereas one enantiomer is used to treat tuberculosis, the other causes blindness.

Naproxen: One enantiomer is used to treat arthritis pain, but the other causes liver poisoning with no

analgesic effect.

Steroid receptor sites also show stereoisomer specificity.

Penicillin's activity is stereodependent. The antibiotic must mimic the D-alanine chains that occur in the

cell walls of bacteria in order to react with and subsequently inhibit bacterial transpeptidase enzyme.

Only L-propranolol is a powerful adrenoceptor antagonist, whereas D-propranolol is not. However,

both have local anesthetic effect.

The L-isomer of Methorphan, levomethorphan is a potent opioid analgesic, while the D-

isomer, dextromethorphan is a dissociative cough suppressant.

(S)-(–) isomer of carvedilol, a drug that interacts with adrenoceptors, is 100 times more potent as beta

receptor blockerthan (R)-(+) isomer. However, both the isomers are approximately equipotent as alpha

receptor blockers.

The D-isomers of amphetamine and methamphetamine are strong CNS stimulants, while the L-isomers

of both drugs lack appreciable CNS(central nervous system) stimulant effects, but instead stimulate the

peripheral nervous system. For this reason, the Levo-isomer of methamphetamine is available as an

OTC nasal inhaler in some countries, while the Dextro-isomer is banned from medical use in all but a

few countries in the world, and highly regulated in those countries who do allow it to be used

medically.

Ketamine is commonly composed of R & S enantiomers that have different dissociative and

hallucinogenic properties, whereas the S enantiomer Esketamine is more potent in isolation as a

dissociative.

Adverse Reactions of isomeric drugs

Isomerism can lead to different therapeutic uses and adverse drug reactions like

Quinine has antimalarial activity while quinidine has an antiarrythmic property.

L-sotalol is alpha-blocker while d-sotalol is antiarrythmic.

Levomethorphan is a potent opiod analgesic while dextromethorphan is a cough suppressant.

R-Thalidomide is sedative while S-Thalidomide has been shown teratogenic effects.

R-Naproxen is used for arthralgic pain while S-Naproxen is teratogenic.

D-Ethambutol is antituberculosis drug while L-ethambutol has been found to cause blindness.

(S) (+)-ketamine causes fewer psychotic emergence reactions, less agitated behavior, and better

intraoperative amnesia, and analgesia than its enantiomer.

L-dopa, used in treatment for Parkinson's disease has an isomer D-dopa which has never been used

because it causes deficiency of white blood cells and thus susceptibility to infections.

Two stereoisomers can compete for binding to same receptors like S-methadone antagonizes

respiratory depression action of R-methadone. If the two isomers are of agonist and antagonist type,

then racemic mixture acts as partial agonist like picendol and sulfinpyrazone inhibits the metabolism of

S-Warfarin significantly but not of R-Warfarin.

References

1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678675/?report=printable

2. http://voh.chem.ucla.edu/vohtar/spring00/30H/pdf/hui.pdf

3. http://www.ncbi.nlm.nih.gov/pubmed/15080761

4. http://www.britannica.com/EBchecked/topic/296365/isomerism