GABA-A or NMDA channels, within the central nervous system (i.e., the brain).
The term anesthesia may therefore be defined as a reversible suppression of sensation
(particularly to pain) with or without loss of consciousness, depending whether it is
local or general anesthesia.
Historically, local anesthetics have been known for many years. Cocaine, the first
such agent, was isolated in 1860 and introduced for clinical application in 1884.
Procaine was developed as a synthetic analog of cocaine in 1905 and lidocaine was syn-
thesized in 1943. The development of new chemical entities as putative local anesthet-
ics remains an ongoing activity in medicinal chemistry.
From a structural perspective, local anesthetic molecules are composed of three
building blocks: a lipophilic (usually aromatic) group connected via an intermediate
alkyl/alkylene chain group (that typically incorporates either an amide or an ester link-
age) to a terminal ionizable group (usually a tertiary amine). This is shown in figure 7.3.
By carefully balancing these three chemical building blocks, a wide variety of different
local anesthetics with varying properties have been designed. The lipophilic portion is
essential for bioactivity. Aromatic groups are strongly preferable to lipophilic nonaro-
matic groups. Structural modifications to the aromatic group profoundly affect the
chemical and pharmacological properties of the local anesthetic molecule. For instance,
an electron-donating substituent in the orthoor para(or both) positions tends to
increase local anesthetic potency. Insertion of methylene or ethylene linkers between
the aromatic group and the carbonyl moiety of either the amide or the ester tends to
decrease bioactivity. The intermediate chain is typically linked directly to the aromatic
ring via the amide or ester and then, more distally, to the terminal ionizable group by a
one–three carbon linker. The insertion of small branching alkyl groups adjacent to
either the amide or ester sterically hinders catabolic cleavage of these moieties, thereby
prolonging the biological half-life. In the lidocaine series, lengthening the chain
between the amide and the tertiary amine from one, to two, to three carbons increases
the pKaof the amino group from 7.7, to 9.0, to 9.5. The terminal hydrophilic ionizable
group is preferentially a secondary or tertiary alkyl amine. However, nitrogen hetero-
cycles such as pyrrolidine or morpholine can also be used.
The local anesthetics can be broadly categorized on the basis of the chemical nature
of the linkage contained within the intermediate alkyl chain group. The amide local
anesthetics include lidocaine (7.5), mepivacaine (7.6), bupivacaine (7.7), etidocaine
(7.8), prilocaine (7.9), and ropivacaine (7.10); the ester local anesthetics include cocaine
(7.11), procaine (7.12), benzocaine (7.13), and tetracaine (7.14). Since the pharmaco-
dynamic interaction of both amide and ester local anesthetics with the same Na+channel
receptor is essentially identical, the amide and ester functional groups are bioisosterically
equivalent. However, amide and ester local anesthetics are not equal from a pharmacoki-
netic perspective. Since ester links are more susceptible to hydrolysis than amide links,
416 MEDICINAL CHEMISTRY
Figure 7.3 Generalized structure of a local anesthetic. Local anesthetics consist of three
fundamental structural units: a lipophilic part, a hydrogen bonding part, and a terminal amine.
The majority of local anesthetic drugs possess these three structural units.