A receptor is a protein that binds a particular molecule.

3. A receptor is a protein that binds a particular molecule. Because a receptor is chiral, it will bind one enantiomer better than the other.

4. Biological Discrimination Adrenergic agents Easson–Stedman hypothesis

5. Activity of (R)-adrenaline, where the three interactive groups are the basic methylamino, the catechol ring, and the secondary alcohol. The corresponding deoxy compound, N-methyldopamine, where the secondary alcohol is removed, was found to have similar activity to (S)-adrenaline, where the hydroxyl group is oriented away from the complementary receptor binding site . Subsequent comparisons of data between pairs of enantiomers and their corresponding deoxy analogs for a number of related adrenergic agents indicated that the Easson–Stedman hyothesis did not always appear to hold.

7. Enantiomers react with achiral reagents at the same rate. Thus, hydroxide ion (an achiral reagent) reacts with R-2-bromobutane at the same rate that it reacts with S-2-bromobutane. • Specific chiral molecules, recognize only one enantiomer, so if a synthesis is carried out using such a chiral reagent or a chiral catalyst, only specific enantiomer will undergo the reaction. One example of a chiral catalyst is an enzyme. • An enzyme is a protein that catalyzes a chemical reaction. The enzyme D-amino acid oxidase, for example, catalyzes only the reaction of the R- enantiomer and leaves the S- enantiomer unchanged.

9. In catalytic hydrogenation if the metal is complexed to a chiral organic molecule, H2 will be delivered to only one face of the double bond. One such chiral catalyst—using Ru(II) as the metal and BINAP (2,2´-bis(diphenylphosphino)-1,1´-binaphthyl) as the chiralmolecule—has been used to synthesize S-naproxen,in greater than 98% enantiomeric excess.

10. Because a receptor typically recognizes only one enantiomer, different physiological properties may be associated with each enantiomer. Receptors located on the exterior of nerve cells in the nose, for example, are able to perceive and differentiate the estimated 10,000 smells to which they are exposed. (R)- -carvone is found in spearmint oil, and (S)-(+) -carvone is the main constituent of caraway seed oil. • The reason these two enantiomers have such different odors is that each fits into a different receptor

11. Many drugs exert their physiological activity by binding to cellular receptors. If the drug has an asymmetric carbon, the receptor can preferentially bind one of the enantiomers. Thus, enantiomers can have the same physiological activities, different degrees of the same activity, or very different activities.

12. Pasteur, in 1858, showed that the mold Penicillium glaucum metabolized (+)-tartrate more rapidly than the (-)-enantiomer (+)-Asparagine tastes sweet, whereas the (-)-enantiomer is insipid. Nervous tissue might itself be dissymmetric. D-amino acids are sweet whereas those of the L-series are either bitter or tasteless.Enantiomers may also differ in their odors. Terpenoid ketones (R)- and (S)-carvone were isolated and shown to have odors of spearmint and caraway, respectively.

13. (R)- and (S)-limonene have odors of orange and lemon respectively. • Odors of (R)- and (S)-amphetamine also differ. • Differences in the activity of atropine [(dl)-hyoscyamine] and (-)-hyoscyamine and (-)- and (+)-adrenaline. • (+)- and (-)-Nicotine also differs markedly in their physiological action. • The DNA double helix and the protein a-helix, the biopolymers have a right-handed turn. • Enzymes and receptor systems exhibit stereochemical preferences.

14. Neurotransmitters,endogenous opioids and hormones are single stereoisomer chiral molecules. • The more active enantiomer takes part in a minimum of three intermolecular interactions with the receptor, whereas the less active enantiomer could interact at two sites only. Thus the fit of the enantiomers to the receptor differs, as does the energy of the interaction. • The anomalies were due to variable indirect activities of the achiral and ‘‘less’’ active enantiomers. • The (-)-enantiomers were found to be more potent than their (+)-enantiomers or deoxy analogs in both normal and reserpine-pretreated tissue. • whereas the (+)-enantiomers and achiral compounds were found to be equipotentincatecholaminedepleted preparations but of variable activity in normal tissue.

15. Easson–Stedman model of the drug–receptor interaction. The more active stereoisomer (top) is involved with three simultaneous complementary bonding interactions with the receptor active site, B_B’, C_ C’and D_D’; its less active enantiomer (lower) may interact at two sites only irrespective of its orientation to the active site.

16. Four-point location model. If the target/binding site(s) protrude from a surface or are in a cleft in the macromolecular structure, then either enantiomer may bind at three sites (e.g., B_ _ B’, C_ _C’, D_ _D’) and the bonding interaction is determined by the approach direction. Alternatively a fourth interaction/location may be required (i.e., A_ _A’or A_ _A’’). The initial interaction may result in conformational changes in structure as proposed in the conformationally driven model.

17. The enantiomer with more pharmacodynamic activity, eutomer, lower affinity, distomer. • The ratio of affinities, eudismic ratio and its logarithm, eudismic index. • The slope of a plot of eudismic index versus the logarithm of affinity, pA2 or pD2 values (in pharmaco- logy or ki and km values in enzymology) for a homologous series is known as the eudismic affinity quotient (EAQ). • The EAQ is a quantitative measure of the stereoselectivity within a compound series for a particular biological effect, positive slope, indicative of greater difference in activity, agonist or antagonist, between a pair of enantiomers, the greater the specificity exhibited by the eutomer.

18. A diastereomeric intermediate must be involved, butthis alone may not be sufficient. A dual action drug, the eutomer may be the distomer in other case. Amosulalol, an adrenoceptor antagonist at both - and - receptors. The (-)-enantiomer is a nonspecific - and selective1- adrenoceptor antagonist, whereas (+)- amosulalol is a selective and more potent1- antagonist. Thus, in the case of amosulalol, the (-)- and (+)-enantiomers are the eutomers for - and -adrenoceptor blockade, respectively.

20. Initial investigations on the enantiomeric effect of isoprenaline on blood pressure in cats and dogs yielded eudismic ratio values for the (-)/(+) of11.8and 87.5, respectively, whereas later studies yielded ratios of 1000 and 450, constant biological activity was a better criterion for enantiomeric purity than constant specific rotation or melting point. -agonist activity resided in the stereoisomer with the R,R absolute configuration and a rank order of potencyR,R >>> R,S > S,R>> S,S.

21. Examination of the pharmacodynamic properties of a pair of enantiomers may yield a number of possible scenarios: • Both enantiomers have similar pharmacodynamic profiles. • The required activity resides in a single stereoisomer, its enantiomer being biologically inert. • The enantiomers may have opposite effects at the same biological targets. • One stereoisomer may antagonize the adverse effects of its enantiomer. • The required activity resides in both stereoisomers, but the adverse effects are predominantly associated with one enantiomer. • The adverse effects are associated with both enantiomers, but the required effect is predominantly associated with one enantiomer.

22. -Methyldopa; the antihypertensive activity resides solely in the S-enantiomer. • The angiotensin-converting enzyme (ACE) inhibitor imidapril is another example: the inactive enantiomer is essentially devoid of activity, a millionfold less active than the eutomer. • Few examples, beneficial activityresides in a single stereoisomer and the adverse effects, or toxicity, reside in its enantiomer. • (+)-methorphan and (-)-propoxyphene are antitussive whereas their enantiomers are analgesics. • Agonist, antagonist.

23. Enantiomers can have opposite actions at the same receptor

24. Ion channels exist in a number of states, depending upon membrane or chemical potential, represent different conformations of proteins, which may influence to the drug binding site. In case of the voltage-dependentcalcium channel, the L-type is sensitive to dihydropyridine derivatives, one enantiomer is more active than the other, some enantiomers have opposite effects on channel function. It is thought that the individual enantiomers interact with different channel states, their binding sites may have opposite stereochemical requirements. Calcium Channel Blocking Agents

26. In the case of ketamine, the beneficial and adverse effects of the drug are predominantly associated with the alternative enantiomers. The drug interacts with multiple binding sites including N-methyl-D-aspartate (NMDA) and non-NMDAglutamate receptors, and muscarinic cholinergic and monoaminergic nicotinic and opioid receptors. The stereoselectivity of the individual enantiomers in terms of both their pharmacological and their clinical effects has been known since late70s. (+)-S-enantiomer has a three- to fourfold greater affinity for the phencyclidine binding site of the NMDA receptor, which is considered to be the primary site of action, than (R)-ketamine. Uricosuricdiuretic agent indacrinone, the diuretic and natriuretic activities reside predominantly in the R-enantiomer, whereas the uricosuric effect is associated with (S)-indacrinone.

27. SSRIs are an important class of antidepressant agents that appear to be better tolerated than the older tricyclic agents and have reduced drug/food interactions compared to the monoamine oxidase inhibitors.

29. Paroxetine and sertraline contain two chiral centers. The latter agent is interesting because of its marked drug selectivity influence. • Trans (+)- paroxetine is a potent inhibitor for serotonin, dopamine, and noradrenaline uptake. • (-)- Paroxetine being selective for noradrenaline inhibition. • Contrast, cis (+)-1S,4S- sertraline, retaining potent, selective serotonin uptake inhibition activity.

30. Stereoselectivity in drug distribution may occur as a result of binding to either plasma or tissue proteins and transport via specific tissue uptake and storage mechanisms.

31. In drug metabolism, stereodifferentiation is the rule rather than the exception,and responsible for the differences in enantioselective drug disposition. • Stereoselectivity in metabolism may arise from differences in the substrate-enzym binding. • As a result, a pair of enantiomers, metabolized at different rates and/or via different routes to alternative products. • Types of metabolism: Substrate selectivity, product stereoselectivity, combination, prochiral to chiral transformations, chiral to chiral transformations, chiral inversion etc.

35. Reduction of chiral sulphoxides or N-oxides to the corresponding sulphides and tertiary amines and their subsequent reoxidation results in the loss and generation of a chiral center, depending on stereoselectivity of the transformations involved, may result inversion. Following administration of vasodilator flosequinan to rats, the alternative enantiomer could be detected in plasma.

36. Enantioselectivity in renal clearance for a number of drugs (modest), In case of diastereoisomers quinine and quinidine, the difference is about fourfold, due to selectivity in protein binding, reabsorption, secretion. Both enantiomers of thalidomide possessed hypnotic activity, whereas the teratogenic activity resided solely in its S-enantiomer. (R)-2-Ethylhexanoic acid was teratogenic, embryotoxic following administration to mice, S-enantiomer,nontoxic and racemate have intermediate response. S-2-n-propyl-4-pentenoic acid, more potent embryotoxin in mice.

38. Male antifertility agents 3-chloropropane-1,2-diol and 3-amino-1-chloropropane-2-ol have indicated that the antifertility activity in rat is due to the S-enantiomers, whereas the R-enantiomers are associated with nephrotoxicity. Its administration to rats resulted in elevated urinary excretion of oxalate, formed via oxidation of the inter mediate 3-chloro pyruvate.