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Stereochemistry The stereochemistry of both the receptor site & the drug molecule helps determine the nature & efficiency of the drug-receptor interaction. Isomers are 2 or more compounds, with the same molecular formula, but have different configurations. They usually differ in chemical, physical or pharmacological properties. Stereoisomers can be divided into 3 main groups: o Optical isomers, o Geometric isomers, o Conformational isomers. I. Optical Isomers: Contain at least 1 asymmetric, or chiral, carbon atom (a carbon atom which is covalently bonded to 4 different substituents). Each asymmetric carbon can exist in 1 of 2 non-superimposable isomeric forms. The 2 enantiomers of 2-hydroxybutane. The chiral carbon is bonded to 4 different groups. The structures shown are mirror images that cannot be superimposed. 1. Enantiomers (Optical antipodes): o Are optical isomers that are mirror images (have at least 1 asymmetric carbon), not superimposable. o Enantiomers have identical physical & chemical properties except that one rotates the plane of polarized light in a clockwise direction (dextrorotatory, designated D or +) & the other in a counter-clockwise direction (levorotatory, designated L or -). o An equal mixture of D and L enantiomers is called a racemic mixture & is optically inactive. o Enantiomers can have large differences in potency, receptor fit, biologic activity, transport & metabolism. E.g., levorphanol has narcotic, analgesic, & antitussive properties, whereas its mirror image, dextrorphanol, has only antitussive activity. o Mutarotation: is a change in the optical rotation of a solution of an optically active compound (common in carbohydrate solutions). H – C – OH HO – C – H H–C–H H–C–H N N H CH3 Dextro (+) H CH3 Levo (-) 1 2. Diastereomers: o Are stereoisomers, which are neither mirror images nor superimposable. o A drug must have at least two chiral centers in order to exist in diastereomers. o Unlike enantiomers, in which all stereochemical centers are opposite, diastereomers have some stereochemical centers that are identical & some that are opposite. o Diastereomers possess different physicochemical properties &, thus, differ in properties, such as solubility, volatility, & melting points. o Ephedrine has 2 assymetric centers & 4 isomers, there are 2 pairs of optical enantiomers: i. 2 pairs are designated ephedrine (levo & dextro) (mirror images). ii. The 2 other pairs are designated pseudo-ephedrine (levo & dextro) (mirror images). iii. However, ephedrine & pseudo-ephedrine are diasteriomers (not mirror images). H – C – OH CH3 – HN – C – H H O– C – H H – C –NH – CH3 CH3 CH3 Dextro (+) Levo (+) Pseudo-ephedrine HO – C – H H – C – OH H – C –NH – CH3 CH3 – HN – C – H CH3 CH3 Levo (+) Dextro (+) Ephedrine 3. Epimers: o Are a special type of diastereomers because all epimers are also diastereomers; however, the opposite is not true. o Epimers are compounds that are structurally identical in all respects except for the stereochemistry about one chiral center. o The process of epimerization (in which the stereochemistry of one chiral center is inverted) is important in drug degradation & inactivation. 2 II- Geometric Isomers (cis-trans isomers) Occur as a result of restricted rotation around a chemical bond, owing to double bonds (or rigid ring systems) in the molecule. o Cis-trans isomers are not mirror images & have different physicochemical properties & pharmacologic activity. o Cis means that both 2 groups are fixed around the double bond so that they are both on the same side of the molecule. (Cis = Z). o Trans means that both 2 groups are fixed around the double bond so that they are on opposite sides of the molecule. (Trans = E). o Because the functional groups of these isomers are separated by different distances, they generally do not fit the same receptor equally well. E.g., cis-diethylstilbestrol has only 7% of the estrogenic activity of trans-diethylstilbestrol. The presence of the double bond allows for the formation of cis & trans isomers CH3 (CH2)7 CH HOOC (CH2)7 CH Oleic acid (Cis configuration - Z) CH3 CH3 CH3 (CH2)7 CH CH (CH2)7 COOH Eliadic acid (Trans configuration - E) CH3 C=C H H C=C H Cis 2 butene (Z) H CH3 Trans 2 butene (E) III- Conformational Isomers (Rotamers or Conformers) 3 o Are non-superimposable orientations of a molecule which result from the rotation of atoms about one or more single bonds. o Ethane has 2 conformational isomers: H H H H H H H H H H H H Staggered Eclipsed o Cyclo-hexane exists in 2 conformers: Boat Chair o Almost every drug can exist in more than one conformation, & this ability allows many drugs to bind to multiple receptors & receptor subtypes. E.g., the trans conformation of acetylcholine binds to the muscarinic receptor, whereas the gauche conformation binds to the nicotinic receptor. The trans & gauche conformations of acetylcholine occur as a result of rotation about the carbon – carbon single bond. trans gauche IV- Bioisosteres 4 o Are molecules containing groups that are spatially & electronically equivalent &, thus, interchangeable without significantly altering the molecules' physicochemical properties. o Isosteric replacement of functional groups can increase potency, decrease side effects, separate biologic activities, & increase the duration of action by altering metabolism. o Additionally, isosteric analogs may act antagonistically to the parent molecule. Procainamide, an amide, has a longer duration of action than procaine, an ester, because of the isosteric replacement of the ester oxygen with a nitrogen atom. Alloxanthine is an inhibitor of xanthine oxidase. It is also an isostere of xanthine, the normal substrate for the enzyme. S N CH2 CH2 CH2N S O CH3 CH3 Phenothiazine ring CH3 CH2 CH2 CH2N CH3 Thioxanthene ring Homologs: When 2 compounds differ only in the length of side chain. S S N CH3 N CH3 CH2 CH2 N CH2 CH2 CH2 N CH3 CH3 N.B. Bioisosters & homologs are not optical isomers. Tautomerism: Keto – Enol form (e.g. Uracil, purine / pyrimidine). 5