Lipophilic Entity

3.1.1. Lipophilic Entity

The various salient features essentially associated with the lipophilic portion (entity) and the anaesthetic activity are as given under :

(a) the presence of an aryl function attached directly to a carbonyl moiety, such as :

amino-ester series ;

Examples : Tetracaine ; Butacaine ; Procaine ; etc., (b) the presence of a 2, 6-dimethylphenyl function usually linked to a carbonyl moiety by means of an imino (—NH—) group, for instance : amino-amide series ;

LOCAL ANAESTHETICS

157 Thus, the amino-ester and the amino-amide series attribute a highly lipophilic property to

the ‘drug molecule’ ; and is believed to afford a substantial contribution towards the binding of local anaesthetics particularly to the channel-receptor proteins. In other words, whatever structural modifications are intended to be carried out in this particular zone of the molecule, it would certainly reflect directly upon the physical and chemical characteristics thereby

causing an appreciable alteration in its local anaesthetic profile ultimately. (c) the effect of electron-donating moieties in the amino-ester series are quite vital and

significant i.e., present in both or para- or ortho-positions. Examples : (i) Amino (—NH 2 ) Function. e.g., Procaine, Propoxycaine, and

Chloroprocaine :

R 1 = – NH 2 ;R 2 = – H : Procaine ; R 1 = – NH 2 ;R 2 = – OC 3 H 7 Propoxycaine ; R 1 = – NH 2 ;R 2 = – Cl ; Chloroprocaine ;

(ii) Alkylamino (RHN) Function : e.g., Tetracaine ;

C HAPTER

Propoxycaine

Proparacaine

Note : All these three functional moieties being electron-donating in nature do help in profusely contributing electron density to the πππππ -clouds of electrons present in the aromatic ring by such effects as — ‘resonance’ and ‘inductive’, thereby increasing ultimately the local anaesthetic potency in comparison to the non-substituted structural analogues, namely : Hexylcaine ; Meprylcaine ;

MEDICINAL CHEMISTRY

(d) the ‘Resonance Effects’ do play a predominant role in explaining specifically the influence of various substituents of the aromatic portion of the molecule upon the ‘local anaesthetic’ actions.

Examples : Possible resonance structures of procaine, lidocaine and tetracaine are as describe below :

(i) Procaine :

The above two structures, I and II, are two resonance forms of procaine, neither of which actually represents the ‘drug’. In fact, a ‘hybrid structure’, wherein the carbonyl moiety attains a partially ionic (not totally as in II), would perhaps be a more probable and correct representation. The aforesaid hypothesis may be further substantiated by varying the an- aesthetic potency of structrural variants vis-a-vis the altered nature of the respective para substituents on the benzene ring ; and relate it to the bond order of the ‘ester carbonyl’ by adequately measuring the corresponding observed IR-stretching frequency, as summa- rized in Table 4.2 below :

Table 4.2. Relationship of Local Anaesthetic Profile and Bond Order

S.No. R-Substituent

IR (C = 0) cm –1

ED 50 (m mol/100 mL)*

0.740 From Table 4.2., it may be observed that both amino and alkoxy functions are regarded as ‘elec-

5 O 2 N—

tron donors’ by virtue of their resonance characteristic ; and, therefore, increase the dipolar (i.e., ionic) nature of the carbonyl (C = 0) moiety. Further, para-substituents do exert a marked and pronounced electron-withdrawing effect in the carbonyl function having more double-bond character and ultimately resulting in less intense local anaesthetic activity.

* Galinsky AM et al. J. Med. Chem., 6 : 320, 1963.

LOCAL ANAESTHETICS

159 (ii) Lidocaine :

In this particular instance i.e., amino-amides, lidocaine analogues, the very strategically positioned O, O′-dimethyl functions are meant to afford adequate protection from amide hydrolysis to ascertain a predicted and desirable duration of action.

In the same vein, one may derive logical conclusions to only justify but also rationalize the possible enhancement in the duration of action of propoxycaine by the presence of ortho-propoxy moiety.

However, in another instance i.e., chloroprocaine, the observed relatively shorter duration of action, in comparison to procaine, may be evidently expatiated by the inductive effect due to the presence of ortho-chloro function, which might help in pulling out the density of electron away from the carbonyl group, thereby rendering it more prone to nucleophilic attack by the plasma esterases.

(iii) Tetracaine : HAPTER

Tetracaine is found to be 50-times more active than procaine. However, this phenomenal enhancement in potency may not be explained and proved experimentally by virtue of the presence of the overwhelming surge in lipid-solubility attributed by the n-butyl moiety marked ‘X’. Logistically, the marked and pronounced potentiation of local anaesthetic profile offered by tetracaine may be attributed to the distinct electron-releasing activity of the said n-butyl function via the inductive effect, that preferentially increases the prevailing electron density of the para-amino moiety, which subsequently enhances the creation of the ‘resonance form’ readily available for enabling to get bound to the viable receptor proteins.