Abstract
Structure–activity relationships (SAR) describe how the structure of related drugs influences their behaviour, for example whether they are agonists or antagonists. In order to understand how differences in drug structure can affect activity it is necessary to appreciate drug development methods and some basic organic chemistry. Once the properties of the contributing groups are understood, then it becomes easier to predict the likely behaviour of a drug molecule compared with the parent drug. In addition, knowledge of the structural properties of a drug may help us appreciate some of their physicochemical properties, such as their solubility in oil and water, their pKa values and whether they are weak acids or bases.
Structure–activity relationships (SAR) describe how the structure of related drugs influences their behaviour, for example whether they are agonists or antagonists. In order to understand how differences in drug structure can affect activity it is necessary to appreciate drug development methods and some basic organic chemistry. Once the properties of the contributing groups are understood, then it becomes easier to predict the likely behaviour of a drug molecule compared with the parent drug. In addition, knowledge of the structural properties of a drug may help us appreciate some of their physicochemical properties, such as their solubility in oil and water, their pKa values and whether they are weak acids or bases. These in turn help us understand the pharmacokinetic behaviour of a drug.
Drug design starts with a lead compound that has the required action in an animal model, but is not necessarily ideal; for example, the drug may resemble a neurotransmitter or be an enzyme inhibitor. By adding various functional groups to this compound it is possible to develop a more specific drug to target the required system. Once a compound with the most favourable pharmacodynamic effects is found, further modifications may be made to make the drug’s pharmacokinetic behaviour more desirable.
In this chapter we will introduce some basic organic chemistry and identify the structures associated with drugs commonly used in anaesthesia. Those basic structures that should be readily identified are mentioned briefly below, together with diagrams of their structures and examples relevant to anaesthesia. These should be used in conjunction with a description of drug activity in Sections II–IV.
Organic chemistry is the study of carbon-based compounds. The position of carbon in the middle of the periodic table (Group IV) gives it an atomic structure that can form covalent bonds with elements from either end of the table. This contrasts with inorganic chemistry, where ionic bonds are most common. Covalent bonds are stronger than ionic bonds and do not interact readily with water, making many organic molecules insoluble in water. By the addition of functional groups (such as hydroxyl, –OH or amine, –NH2) these organic compounds can become water-soluble. Organic molecules are the basis of life, from DNA to structural proteins and chemical messengers. Knowledge of these basic building blocks and signalling systems is crucial to an understanding of how therapeutic agents modify existing physiological processes at the molecular level.
Building Blocks: Amino Acids, Nucleic Acids and Sugars
Amino Acids
The basic structure of an α-amino acid is a hydrocarbon group with both a carboxyl and amine group attached to the end carbon (the α-carbon). There are 20 commonly occurring α-amino acids that form the building blocks for protein synthesis (of which five cannot be synthesised – the essential amino acids). Not all amino acids form peptides and proteins; some amino acids are important precursors in neurotransmitter synthesis. For example, phenylalanine can be metabolised to tyrosine which then enters adrenergic neurones as the substrate for catecholamine synthesis (see Chapter 13). Other α-amino acids are central neurotransmitters in their own right, for example, glycine and glutamate. Not all amino acids of importance are α-amino acids. GABA (γ-amino butyric acid), as its name suggests, is a γ-amino acid that has the carboxyl and amine groups on opposite ends of a butyl backbone; GABA is an important inhibitory neurotransmitter.
Nucleic Acids, Nucleosides and Nucleotides
Nucleosides are formed from the combination of a nucleic acid with a sugar, usually ribose (e.g. adenosine, guanosine). Nucleotides are the building blocks of DNA/RNA and are formed from nucleosides linked to a phosphate group. The nucleic acids are either purines (adenine or guanine) or pyrimidines (cytosine, uracil or thymine). Many anti-cancer drugs are analogues of nucleic acids or nucleotides. Nucleosides are important intermediates in metabolic processes as they can combine with high-energy phosphate groups to act as co-factors in metabolic and catabolic processes within the cell.
Sugars
These are carbohydrates with a chemical formula (CH2O)n, where n can be 3 (a triose, e.g. glyceraldehyde), 4 (a tetrose), 5 (a pentose, e.g. ribose) or 6 (a hexose, e.g. glucose). They are naturally occurring compounds and glucose is metabolised to carbon dioxide and water through oxidative tissue respiration. The pentoses and hexoses exist in cyclic forms in vivo.
Drugs and their Structures
Many drugs are organic molecules and often derived from plant material. It is not possible here to describe all the molecular structures of groups of anaesthetically important drugs. In this section the following selected structures will be described: catecholamines, barbiturates, benzodiazepines, non-depolarising muscle relaxants (bis-benzylisoquinoliniums and aminosteroids) and opioids.
Catecholamines and Derivatives
These are derived from the amino acid tyrosine (see also Figure 13.3), which is hydroxylated (addition of an –OH group) and decarboxylated (removal of a –COOH group). The side chain (ethylamine) consists of two carbons attached to an amine group. The α-carbon is bound to the amine group and the β-carbon is covalently linked to the catechol ring. The size and nature of the functional groups on the terminal amine and the α-carbon determine whether an agent is active at either α- or β-adrenoceptors or is an agonist or antagonist. In addition, only catechols (two adjacent –OH groups on the benzene ring) are metabolised by catechol-O-methyl transferase (COMT); derivatives without this feature may have a longer duration of action. Similarly, monoamine oxidase (MAO) will metabolise only drugs with a single amine group, preferably a primary amine, although adrenaline, a secondary amine (see mini-dictionary below), is a substrate (see Chapter 13).
Barbiturates
Barbiturates are derivatives of barbituric acid, which is formed by a condensation reaction (i.e. water is also formed) between malonic acid and urea. Barbiturates are weak acids, but also have imino groups present (see Figure 9.3). Thio barbiturates have, as their name suggests, a thio (=S) substitution for the keto group (=O). The types of hydrocarbon groups on the 5-carbon determine the duration of pharmacological action. Oxybarbiturates undergo less hepatic metabolism than the corresponding thiobarbiturate.
Benzodiazepines
Members of this group of heterocyclic compounds are interesting in that structurally they have both six- and seven-membered rings, and some also have a five-membered ring. Their C-containing ring structures make benzodiazepines (BDZs) poorly water-soluble and diazepam requires a special lipid emulsion preparation (diazemuls) to be used intravenously. However, by altering the hydrocarbon groups and pH, an alternative tautomeric form without a closed seven-membered ring can be formed. Thus midazolam is presented in the ampoule as a water-soluble drug, but when it reaches the plasma it returns to the more lipid-soluble ring form (see Figure 18.1). There are three groups of BDZs: 1,4-BDZs (diazepam, temazepam, lorazepam), heterocyclic BDZs (midazolam) and 1,5-BDZs (clobazam). Some of the 1,4-BDZs are metabolically related; diazepam is metabolised to oxazepam and temazepam.
