YEREVAN STATE MEDICAL UNIVERSITY AFTER M. HERATSI DEPARTMENT OF PHARMACY Balasanyan M.G. Zhamharyan A.G. Afrikyan Sh. G. Khachaturyan M.S. Manjikyan A.P. MEDICINAL CHEMISTRY MANUAL (part 2) YEREVAN 2020 1 LOCAL ANESTHETICS Similar to many modern drugs, the initial leads for the design of clinically useful local anesthetics (LA) were derived from natural sources. Since 15th century it was known that Erythroxylon Coca plant leaves possess anesthetic properties. The active principle of the coca leaf however was not discovered until 1860 by Niemann, who obtained a crystalline alkaloid from the leaves, to which he gave the name cocaine. Koller introduced cocaine into clinical practice in 1884 as a topical anesthetic for ophthalmological surgery. After cocaine releasing, discovering the structure and synthesis, became clear that it represents methyl ecgonine benzoate, which is easily hydrolyzed (especially during sterilization in high temperature), forming ecgonine, benzoic acid and methanol. COOCH3 N CH3 O C O Cocaine had one big disadvantage: its toxicity was very high. Studies of the cocaine biological activity and its hydrolysis products have shown that local anesthetic activity is due to anesthesiophor group, which includes the following structural parts: 1. aromatic ring (with radicals), which gives lipophilic properties to the molecule, 2. aliphatic amino group, which is responsible for the molecule’s hydrophilic properties, 3. intermediate chain, which connects molecule’s lipophilic and hydrophilic components. Chemically it represents benzoic acid connected with different groups (Rs-different aliphatic radicals) by ester, amide or thio ether bonds (X=O, NH, S). R''' R' Ar C X (C)n N R'' O R'''' Each of this components’ role have been studied on the anesthetic activity. It becomes clear, that the aromatic ester group is so important; scientists thought that all aromatic esters have an anesthetic activity. Therefore, many derivatives of benzoic acid have been synthesized, majority 2 of which possess high anesthetic activity and low toxicity. Anesthesin is an example of this group, which represents ethyl ester of para-amino benzoic acid (PABA). O H2N C O C2H5 Anesthesin This compounds’ disadvantage is that practically used their soluble salts possess strong acidic reaction, in which result they are used in form of water insoluble bases, which can’t be used for infiltration or transmitting anesthesia and can be used only for superficial anesthesia, in powders, ointments forms for ulcers, burns and mucous inflammation anesthesia. Having a goal to increase PABA alkyl ethers water solubility, tertiary amino group inserted in the molecule alcoholic part. This amino group insertion increases these ethers basic properties, giving chance to get salts, solutions of which don’t have acidic reaction, but it’s near to basic. Besides, tertiary amino group insertion in the ester’s molecule increases their anesthetic properties. PABA diethylamino ethanolic ester hydrochloride (designed according to this principle) is well known in literature under Novocain or procaine names. Novocain also has anesthesiophor group, but it is not free from side effects: it has anti-sulfanilamide effect, causes allergic reactions. Its local anesthetic effect is quite short and it can’t be used for superficial anesthesia. Due to these reason new local anesthetics synthesis continues and doesn’t stop. O C2H5 .HCl H2N C O CH2 CH2N C2H5 Novocain It was very important to study interaction types between Novocain and its corresponding receptor for new local anesthetics synthesis. It was found, that there are different bonds between receptor centers and molecule different parts (charge transfer: induced dipole, dipole-dipole interaction, hydrogen bond, van der Waals interactions and hydrophobic interaction and ionic bond). 3 SAR Changes in the aromatic ring In all local anesthetics as in Novocain carbonyl group’s activity and binding force with the receptor depends on carbon atom partly positive charge, due to which conjugation is possible between double bond’s π-electronic cloud and aromatic ring π framework to delocalize toward carbonyl group carbon atom. Insertion of an electron-donating substituent in the aromatic ring increases carbon atom partly positive charge, due to which binding with the receptor is stronger which leads to stronger local anesthetics effect. Electron acceptor substituent (for example nitro group) decreases or loses local anesthetic property. Insertion of a methylene group between the aromatic moiety and carbonyl function is undesirable. 4 Local anesthetic activity increases in case of amino group presence in the para-position of the aromatic ring (Novocain). NH2 substitution by NHR or NR2: anesthetic activity increases when R extends up to C3; C3-C6 activity remains and more than C6 sharply decreases. According to this Dicaine was created, which represents dimethylamino ethyl ester of para-butylamino benzoic acid. Dicaine Changes in the intermediate chain The distance between ester oxygen and amino group’s nitrogen is very important for the local anesthetic activity, which is detected by the carbon atoms number in the alcohol chain. The elongations and branching of this chain increase local anesthetic activity, also toxicity (local, general) sharply increases. Local anesthetic activity increases also in cyclic group presence in this part, but these compounds are not used either, because they have strong irritative properties. Corresponding amides are obtained substituting ester oxygen by NH, the most of which show higher activity, than isosteric esters, but their toxicity also is high. From these compounds Sovcain is used, but it requires great caution because of high toxicity. C2H5 O NH CH 2 CH2 N C C2H5 N OC4H9 Sovcain 5 Novocain’s corresponding isosteric amide, which is known under the name of Novocainamide has low expressed local anesthetic activity, but has very high anti-arrhythmic effect. Novocain thioisoster - Thiocain has 3 times higher local anesthetic activity. O O C C2H5 C C2H5 NH CH 2 CH2 N S CH 2 CH2 N C2H5 C2H5 H2N H2N Novocainamide Thiocain Changes in the aliphatic amino group Chain elongation increases local anesthetic effect and local irritative property. Branching decreases toxicity, and local anesthetic effect. Cyclic radicals were inserted; nitrogen in a cycle, etc. Tertiary amino group can be represented in heterocycle. Benzoic and para-amino benzoic esters were studied which contain heterocyclic radicals, such as pyrrole, pyrroline, piperidine, piperazine etc. Piperidine derivatives are the most interesting. Benzoate methylpiperidinpropanol- meticain is one of the strongest local anesthetics now. H2C CH2 CO O CH2 CH 2 CH2 N CH2 CH CH2 H3C Meticain Amino acids amides are very interesting from which lidocaine has expressed local anesthetic effect, which is known as xylocaine. Lidocaine Trimecaine Action Mechanism Local anesthetics prevent nerve impulse formation and transmission. They block sodium channels, inhibit action potential formation and nervous impulse isn’t transmitted. Now it is known that there are specific receptors in the sodium channels, to which local anesthetics are bound. 6 Way of reaching to the receptor depends on their physico-chemical properties: molecule size, pK, solubility and binding by the chemical properties. Protonized molecules and quaternary ammonium compounds reach to their targets through the external hydrophilic way, which is possible only during channel activation. Lipophilic anesthetics are diffused across the nerve membrane in basic, uncharged state. They can reach to the receptor immediately: in their basic uncharged form- by hydrophobic way, also they can bind with medium protons and reach to the receptor after protonization - by hydrophilic way. There is a hypothesis, according to which local anesthetics receptors represent acidic phospholipids, to which local anesthetics bind (especially with lecithin). Let’s study that binding for Novocain and receptor example; it is carried out: a) via ion –dipole interaction, where ionic group and polarized group take part in the bond formation. b) via hydrophobic bond where lipophilic groups take part. Hydrogen bonds are also formed, the stronger is the bond the longer is local anesthetic effect. It is known, that local anesthetics compete with Ca, which binding with the acidic phospholipids regulates sodium permeability through the nervous membrane. Local anesthetics forming mentioned above bonds displace Ca, causing cellular membrane structural and functional changes and impulse transmission is inhibited. A lot of local anesthetics can form a π-complex with thiamine, where the anesthetic appears as an electro donor and thiamin as an acceptor. As it is known, thiamin and its precursors (phosphate ethers) have fundamental importance in nerve excitability. Local anesthetics forming thiamine complex, block nervous transmission and develop local anesthesia. 7 Classification All local anesthetics can be divided into 2 groups: Ester derivatives. There are esters of the following acids: benzoic acid, para-amino benzoic acid, meta-amino benzoic acid or para-alkoxy benzoic acid. As esters drugs of this group easily undergo hydrolysis in vivo and in vitro losing their activity. More common classification is: a) benzoic acid derivatives, cocaine, isobucaine, pribecaine, propanocaine, etc. b) amino benzoic acid derivatives, betoxycain, novocain, tetracaine, benzocaine, etc. Amide derivatives. This group includes 3 subgroups: a) basic amides - dibucaine,