Stereochemistry and Biologic Activity

6.3. Stereochemistry and Biologic Activity

An intensive and extensive research carried out till date on ‘drug-design’ has not only established but also paved the way in the specialized aspect of ‘stereochemistry’ of the ‘targetted-drug molecules’. This particular approach has inspired the ‘medicinal chemist’ to tailor-made such newer drug substance(s) in which the proper strategical positioning of various functional moieties are introduced (or inducted) so that they are capable of interacting optimally with either an enzyme or a receptor.

*E and Z-isomer : When the two aromatic heterocyclic rings are on the same side of the molecule, having the

double-bond, it is known as the cis-or Z-isomer (from the German zusamer or ‘‘together’’) ; when these are located on opposite sides the designation is trans- or E -isomer-(from the German entagegen or ‘‘opposite’’).

MEDICINAL CHEMISTRY

Interestingly, the following five different aspects of stereochemistry (i.e., types of isomeric drugs) shall now be discussed in the sections that follows :

6.3.1. Positional Isomers (or Constitutional Isomers)

In this specific instance the compounds essentially possess the same emperical formula but the atoms of the molecule are rearranged in an altogether different order.

Examples :

(1) Pentobarbital and Amobarbital :

These positional isomers (I) and (II) belong to the barbiturate family. However, these positional isomers specifically differ only in the formation of the 5-carbon side chain attached to the C-5 position to the barbiturate ring system. Thus, compound (I) is a short-acting barbiturate ; whereas, compound (II) is an intermediate-acting barbiturate.

(2) Terbutaline and N-tert-Butyl norepinephrine :

The resorcinol residue in (III) has predominantly catered for as a biologically effective replacement of the catechol moiety present in (IV). Importantly, the resorcinol structural analogue (III), in a striking contrast to the catechol (IV), is not a substrate for catechol-O-methyltransferase (COMT)-an extremely important metabolic enzyme ; and hence, it possesses a marked and pronounced longer duration of

action. In fact, terbutaline serves as a useful selective (βββββ 2 -adrenergic stimulant for the treatment of bronchial asthma and related physiological conditions (administered orally).

6.3.2. Geometrical Isomers

In geometrical isomers there exists a spatial arrangement of either atoms of functional groups in the carbon-carbon double bond locations, which has been duly expatiated earlier as under :

(a) section 5.2 i.e., non-cyclic analogues of oestradiol, and (b) section 6.2 i.e., diastereoisomers example (ii).

PHYSICAL-CHEMICAL FACTORS AND BIOLOGICAL ACTIVITIES

6.3.3. Absolute Configuration

The terminogloy ‘absolute configuration’ particularly refers to the arrangement of atoms in space of a chiral compound. It has been observed that there is a stark and distinct difference in specific

biologic activity of the optical isomers (enantiomers) having the (R) and (S) configuration. A typical HAPTER example of Levorphanol and Dextrorphan has already been discussed under Section 6.2 in this chapter.

6.3.4. Easson-Stedman Theory*

According to this theory put forward in 1974, the relative order of activity of the ‘isomers’ viz.,

R(–) isomer epinephrine, S(+) isomer epinephrine and epinine deoxy isomer on the adrenergic

receptors are in the order of R > S ~ deoxy. Besides, the R isomer can bind to all the three sites, namely : (i) catechol binding site ‘A’ ; (ii) hydroxy binding site ‘B’ ; and (iii) anionic binding site ‘C’ as

illustrated below ; whereas ; the S isomer and the deoxy isomer, that essentially exhibit practically identical biological activity, can exclusively bind to two of the sites.

6.3.5. Conformationally Flexible to Conformationally Rigid Molecule

A vital, useful and latest strategy invariably employed and practised in ‘drug design’ of ‘newer targetted drug molecules’ by most of the ‘medicinal chemists’ involves essentially of converting a rather conformationally flexible molecule into a conformationally rigid molecule so as to establish and find the optimized conformation that is required for binding to a drug receptor. This particular scientific and logical approach certainly helps in revealing certain cardinal aspects in ‘drug design’, such as :

■ in incorporating selectivity for receptors ■ to minimise and eliminate undesired side effects ■ to learn more with regard to spatial relationships of functional moieties for receptors. Example : The aforesaid critical and important aspect may be expatiated with the aid of the

following example of DOPAMINE, which enhances cardiac output by stimulating βββββ-receptors.

*Patil, PN et al. Pharmacol. Rev. 26 : 232, 1974

MEDICINAL CHEMISTRY

In reality, dopamine (I) may exist in an infinite number of conformation about the single side- chain C—C bond. However, two such conformations, namely : (II) [θ = 60° gauche] and (III) [θ = 180° gauche ], both having trans-conformation may show the maximum biological activity.