Alkaloids SUBJECT FORENSIC SCIENCE

SUBJECT FORENSIC SCIENCE

Paper No. and Title PAPER No. 9: Drugs of Abuse

Module No. and Title MODULE No. 33: Alkaloids

Module Tag FSC_P9_M33

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

TABLE OF CONTENTS

1. Learning Outcomes

2. Introduction

3. Forensic Significance

4. Chemical Properties of Alkaloids

5. Classification of Alkaloids

6. Some Notable Alkaloids of Forensic Importance

7. Summary

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

1. Learning Outcomes

After studying this module, you shall be able to know about-

 The significance of Alkaloids  Classification of Alkaloids and importance of some notable Alkaloids  Forensic importance and examination of Alkaloids

2. Introduction

Alkaloids are a group of molecules with a comparatively large occurrence in nature around the world. They are very diverse chemicals and biomolecules, but they are completely secondary compounds and they are derivative of amino acids. However, an exact definition of the word ‘alkaloid’ (alkali-like) is slightly difficult because there is no clear-cut borderline between alkaloids and naturally occurring complex amines. The term alkaloid was coined in 1819 by the pharmacist W. Meisner and meant simply, alkali like. Typical alkaloids are derived from plant sources, they are basic, they comprehend one or more nitrogen atoms, generally existing in a heterocyclic ring, and they habitually have a noticeable physiological action on human or other animals. The term ‘proto-alkaloid’ or ‘amino-alkaloid’ is occasionally applied to compounds such as hordenine, ephedrine and colchicine which lack one or more of the properties of typical alkaloids. Alkaloids are organic bases.

A “True Alkaloid” can be regarded as by:

 The possession of a nitrogen atom as part of a heterocyclic system;  A multifaceted molecular structure;  Significant pharmacological properties;  Its origin from the plant kingdom

The majority of alkaloids fit this four part definition; however, a number of exceptions exist. The compounds Samandarine, Samandarone, and Cycloneosamandarine, secluded from the dermal glands of the European Fire Salamander displays the usual properties of an alkaloid substance, but do not fit the definition of a “true alkaloid” owing to their animal origin. True alkaloids are of rare occurrence in lower plants. In the fungi the lysergic acid derivatives and the sulphur-containing alkaloids, e.g. the gliotoxins, are the best known. Many alkaloids are poisonous, others are addictive (e.g. cocaine), and some are used clinically (e.g. morphine). More than 10,000 alkaloids are currently known, the first discovered being Narcotine, isolated from opium.

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

Alkaloids are constituents very well recognized for their biological action at the commencement of world evolution. They were used in traditional herbal medication for the treatment of ailments and in weapons as venoms in the course of tribal wars and during hunting. After the discovery of the first alkaloid, narcotine, other alkaloids were rapidly discovered like Morphine form opium, strychnine from Strychnos nux-vomica seeds, emetine from ipecacuanha root, quinine from Cinchona bark and coniine from hemlock. Alkaloids are used medicinally in their own right e.g. hyoscyamine and vinblastine and they have often provided lead compounds for the development of synthetic drugs. For example, cocaine was the first local anaesthetic, quinine the first antimalarial and tubocurarine the first neuromuscular blocking agent. Alkaloids frequently have powerful physiological effects. Most alkaloids are colourless, crystalline compounds: e.g. coniines, but some such as nicotine and hygrine, are liquids. Usually, many are optically active in nature and the various active forms are generally found but not in different plants. Alkaloids are produced by secondary metabolism of primary metabolites, usually amino acids. These pathways are long, intricate, stereochemically precise and energy consuming, and are assumed to be of evolutionary benefit.

3. Forensic Significance

The poisonous and therapeutic effects of plants have been known since time immemorial, but the active constituents have been studied for only about 200 years. In most human history, alkaloids from plant extracts have been used as ingredients in potions (liquid medicine) and poisons. Ancient people used plant excerpts containing alkaloids for the treatment of a large number of diseases such as snakebite, fever and insanity. Habitually the bioactive compounds in the plants that intrigue the chemist are the nitrogen containing bases called alkaloids. Alkaloids have complex molecule structure and they have significant pharmacology activities. Alkaloids are time and again toxic to man and have many intense physiological actions, hence their wide used in medicine. For examples, cinchona alkaloids which, is existing in the bark of Cinchona species and Remijia species consisted of quinine as their main constituents which has been known as anti- malarial agent. Alkaloids have delivered a means of pharmacologically active compounds. Approximately 25% of the drugs used at present are of plant origin. These are administered either as pure compounds or as extracts and have often served as model structures for synthetic drugs.

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

4. Chemical Properties of Alkaloids

Maximum alkaloids are well-defined crystalline substances which bond with acids to form salts. In the plant they may exist in the free- state, as salts or as N -oxides. In addition to the elements carbon, hydrogen and nitrogen, most alkaloids contain oxygen. A small number of alkaloids, such as coniine from hemlock and nicotine from tobacco, are oxygen-free and are liquids. Even if coloured alkaloids are comparatively uncommon, they are not unknown; berberine, for example, is yellow and the salts of sanguinarine are copper-red.

5. Classification of Alkaloids

5.1 CLASSIFICATION BASED UPON THE BIOGENESIS:

Alkaloids show great variety in their botanical and biochemical origin, in chemical structure and in pharmacological action. Consequently, many different systems of classification are possible and the classification mentioned hereinafter is not exhaustive. Alkaloids can be classified by their mutual molecular precursors, founded on the biological pathway used to build the molecule. From a structural perspective, alkaloids are separated according to their shapes and origins. There are three main types of alkaloids:

(1) True alkaloids (2) Protoalkaloids (3) Pseudoalkaloids

True alkaloids and Protoalkaloids are derived from amino acids, whereas pseudoalkaloids are not derived from these compounds.

5.1.1 True alkaloids

True alkaloids are derived from amino acids and they share a heterocyclic ring with nitrogen. These alkaloids are extremely reactive substances with biological activity even in small doses. All true alkaloids have a bitter taste and appear as a white solid, with the exception of nicotine which is a brown liquid. True alkaloids form water-soluble salts. Furthermore, most of them are crystalline substances which bond with acids to form salts.

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

True alkaloids may occur in plants in the Free State, as salts and as N-oxides. These alkaloids befall in a narrow sum of species and families, and are those compounds in which decarboxylated amino acids are condensed with a non-nitrogenous structural moiety. They are typically found as salts in plant such as liriodenine and morphine.

5.1.2 Protoalkaloids

Protoalkaloids are compounds, in which the N atom derived from an amino acid is not a fragment of the heterocyclic ring. Such kinds of alkaloid include compounds derived from l- tyrosine and l-tryptophan. Protoalkaloids are of a closed ring, being impeccable but structurally simple alkaloids. They are not restricted to any specific class of alkaloids and are often classified according to the amino acids from which they are derived. They form a minority of all alkaloids. Hordenine, mescaline and yohimbine are good examples of these kinds of alkaloid.

5.1.3 Pseudoalkaloids

Pseudoalkaloids are compounds of elementary carbon skeletons of which are not derived from amino acids. They can also result from the amination and transamination reactions of the different pathways coupled with precursors or post-cursors of amino acids. These alkaloids can also be derived from non-amino acid precursors. The N atom is introduced into the molecule at a relatively late stage, for example, in the case of steroidal or terpenoid skeletons. Pseudoalkaloids can be acetate and phenylalanine derived or terpenoid, as well as steroidal alkaloids. Examples of pseudoalkaloids include such compounds as coniine, capsaicin, ephedrine, solanidine, caffeine, theobromine and pinidine.

5.2 CLASSIFICATION BASED UPON THE RING SYSTEM

It is perhaps the most extensively established and mutual approach of classification of alkaloids for which the principal condition is the presence of the basic heterocyclic nucleus. According to this concept, the alkaloids are classified on the basis of the ring system present in them.

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

5.2.1 PYRROLIDINE ALKALOIDS

Pyrrolidine alkaloids have a pyrrolidine (C4N skeleton) nucleus. The structural α of these alkaloids is l-ornithine (in plants) and l-arginine (in animals). e.g., Hygrine

Pyrrolidine Ring System

5.2.2 PIPERIDINE ALKALOIDS

Piperidine alkaloids contain the piperidine nucleus. True piperidine alkaloids have one-

cycle compounds with the C5N nucleus. One of the characteristics of piperidine alkaloids is the Odour. Moreover, they are neurotoxins which have acute effects such as chronic toxicity. e.g., Lobeline

Piperidine Ring System

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

5.2.3 PYRROLIZIDINE ALKALOIDS

The pyrrolizidine nucleus is characteristic of this group of alkaloids. e.g., Senecionine

Pyrrolizidine Ring System

5.2.4 TROPANE ALKALOIDS

Tropane alkaloids have a tropane (C4N skeleton) nucleus. Structurally, these alkaloids synthesize as post-cursors of pyrrolines. Characteristic tropane alkaloids (e.g., atropine, hyoscyamine, cocaine, tropinone, tropine, littorine and cuscohygrine) have a strong biological activity, especially as neurotransmitters.

Tropane Ring System

5.2.5 QUINOLINE ALKALOIDS The alkaloids containing principally the ‘quinoline’ nucleus comprise a series of alkaloids obtained exclusively from the Cinchona bark. These alkaloids possess the basic skeleton of 9’-rubanol that is derived from the parent compound known as Ruban. The major members of this particular group are, namely: quinine, quinidine, cinchonine and cinchonidine.

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

Quinoline Ring System

5.2.6 ISOQUINOLINE ALKALOIDS

The Isoquinoline alkaloids are a huge class of medicinally active alkaloids whose properties are variable. Their properties include being anti-spasmodic, anti-microbial, anti-tumour, antifungal, anti-inflammatory, antiviral, amoebicidal and anti-oxidant and can also act as enzyme inhibitors. This class notably includes morphine and codeine. They are derived from the amino acids phenylalanine or tyrosine. They are formed from a precursor of 3, 4- dihydroxytyramine (dopamine) linked to an aldehyde or ketone.

Isoquinoline Ring System

Examples: Opium alkaloids (Papaverine, Narcotine, Narceine), Pancratistatin, Sanguinarine, Hydrastine, Berberine, Emetine, Berbamine, Oxyacanthine.

5.2.7 INDOLE ALKALOIDS

This structural group of indole alkaloids contains Indole ring. E.g., tryptamine, serotonin, Ergometrine, psilocin and psilocybin. Indole alkaloids form a very important group from the perspective of their application.

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

Indole Ring System Examples, Tryptamines : Serotonin, Bufotenine, Psilocybin Ergolines : Ergine, Ergotamine, Lysergic Acid Beta Carbolines : Harmine, Harmaline, Tetra Hydro Harmine Yohimbans : Reserpine, Yohimbine Vinca alkaloids : Vinblastine, Vincristine Kratom alkaloids : Mitragynine, 7- Hydroxy Mitragynine Tabernanthe iboga : Ibogaine, Voacangine, Coronaridine Strychnos nux-vomica : Strychnine, Brucine

5.2.8 IMIDAZOLE ALKALOIDS

Imidazole alkaloids contain an imidazole ring structure in them. This group of alkaloids is an exception in the transformation process of structures, because the imidazole nucleus is already made at the stage of the precursor. Alkaloids from this group include, for example, Dolichotheline, Pilocarpine and Pilosine.

Imidazole Ring System

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

5.2.9 PURINE ALKALOIDS

The Coffee plant family contains two major purines of adenine/guanine derived alkaloids, the so-called “purine alkaloids”. Purine is a nitrogenous base of nucleotide, which consists of just purine and pentose sugar (d-ribose or 2 deoxy-d-ribose). Typical purine alkaloids are Caffeine, Theophylline and Theobromine. The same or similar purine alkaloids occur also in other plant families.

Purine Ring System

5.2.10 STEROIDAL ALKALOIDS

Steroidal alkaloids ascend by the presence of basic nitrogen at some point in the steroid molecule. e.g., Solanidine;

Steroid Ring System

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

6. Some Notable Alkaloids of Forensic Importance

6.1 Ephedrine

Various species of Ephedra are used as a source of the alkaloids ephedrine and pseudoephedrine. Ephedrine is used for the relief of Asthma and Hay Fever. Its action is more protracted than that of adrenaline, and it has the additional advantage that it need not be given by injection but may be administered by mouth. In oriental medicines, the ephedras are also used as anti-inflammatory drugs and this action is attributed to an Oxazolidone related to Ephedrine. Ephedrine may be applied in the treatment of oedema in insulin-dependent diabetics.

6.2 Coniine

Coniine was the first alkaloid to have its structure recognized and to be synthesized. Piperidine alkaloids such as Coniine and Coniceine are very poisonous. They occur in hemlock (Conium maculatum), known as a very toxic plant. Cases of death by respiratory failure resulting from coniine alkaloids are frequently reported. The classic toxic symptoms of coniine alkaloids range from paralysis, muscular tremors, muscle weakness and respiratory failure preceding death. When hemlock is treated with solution or potassium hydroxide, it develops a strong, mouse-like odour owing to liberation of the alkaloid coniine.

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

6.3 Nicotine

Nicotine is a significant insecticide, and large quantities of it are prepared from those parts of the tobacco plant which cannot be used for tobacco manufacture. Nicotinic acid provides alkaloids with the pyridine nucleus in the synthesizing process. This nucleus appears in such alkaloids as Anabasine, Anatabine, Nicotine, Nornicotine, Ricine and Arecoline. Nicotine is used in countless products on the pharmaceutical market. At least 20 different products are known to contain Nicotine.

6.4 Atropine

A chief source of Atropine is from the plant Atropa Belladonna. Atropine has a stimulant action on the Central Nervous System and depresses the nerve endings to the secretory glands and plain muscle. Atropine blocks muscaric cholinergic receptor competitively and has a large spectrum of clinical applications. Atropine acts as a parasympatholytic on parasymphathetically innervated organs. Therefore, the possible applications of atropine are as a general anaesthetic and include its use in pure form or as a component.

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

6.5 Quinine

The pharmaceutical drug industry has succeeded in the use of natural plant alkaloids for the development of antimalarial agents like Quinine. It is acquired from the bark of Cinchona plant. Also, because the nucleic acid synthesis is inhibited by the DNA intercalation quinine has a schizonticide activity. This activity is also based on carbohydrate metabolism. Quinine can be used in the treatment of myotonic disorders. Quinine can be found in drugs such as Adaquin or Biquinate. These drugs are important in the prevention and treatment of malaria.

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

6.6 Cinchonine

Cinchonine is obtained from a variety of Cinchona bark, especially in the bark of Cinchona micrantha belonging to family Rubiaceae. The basic skeleton of Cinchona alkaloids is Ruban-9-ol. Ruban nucleus is a combined skeleton formed from a quinoline ring attached through a methylene group to a quinuclidine ring (a bicyclic ring contain N). Cinchonine and Cinchonidine are used as an anti-rheumatic.

6.7 Morphine

The plant family Papaveraceae contains l-tyrosine derived alkaloids such as Morphine, Codeine, Thebaine, Papaverine, Narcotine, etc. The opium poppy (Papaver somniferum) is a well-known source of opium from its latex. The Poppy family alkaloids have strong biological and medicinal impact. They are also strong narcotics. The morphine molecule has both a phenolic and an alcoholic hydroxyl group, and when acetylated forms diacetyl morphine or heroin.

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

6.8 Codeine

Codeine is ether of Morphine (Methylmorphine), and other morphine ethers which are used medicinally are Ethylmorphine and Pholcodine. Codeine is a constituent of at least 250 pharmaceutical products on the market.

6.9 Strychnine

Strychnine, obtained from the plant Strychnos nux vomica, is an extremely toxic alkaloid. Glycine gets accommodated when strychnine binds itself to receptor sites in the spinal. Brucine is a dimethoxy form of Strychnine, and is less toxic. Strychnine may also cause convulsions and disorders of the CNS.

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids

7. Summary

 The alkaloids are defined as the basic nitrogenous complex organic compounds available naturally in the plant and animals.  Generally, Alkaloids contains a heterocyclic ring in their molecular structure but non- heterocyclic structures have also been reported.  The very first technique employed for the analysis of alkaloid was developed in the year 1805 for morphine. Morphine and codeine are natural products of Papaver somniferum. However, the codeine is naturally produced in small amounts.  Alkaloids are found essentially in the plants of the Dicotyledonous families. They occur in certain parts of the plants like leaves, fruits, seeds, bark and roots.  Most of the alkaloids have been colourless (except Berberine), crystalline, non- volatile solids (except Coniine and Nicotine) and bitter in taste.  Alkaloids are basic and go through reaction with acids to form alkaloidal salts. The alkaloids are unbound from their salts by adding alkalis.  Morphine and codeine N –oxides, are natural constituents of the opium poppy latex, and Nicotiana species contain two isomeric nicotine N– oxides, based on the pyrrolidine nitrogen.  Cocaine was the first local anaesthetic and Quinine the first antimalarial and Tubocurarine the first neuromuscular blocking agent.  Alkaloids can be precipitated by following reagents: i. Mayer’s Reagent ii. Dragendorff’s Reagent iii. Hager’s Reagent iv. Wagner’s Reagent v. Merme’s Reagent vi. Somenschein’s Reagent vii. Scheibler’s Reagent viii. Tannic Acid Solution

FORENSIC SCIENCE PAPER No.9: Drugs of Abuse MODULE No.33: Alkaloids