Isomerism Flashcards
Isomerism
Definition, classes (2)
= the phenomenon by which molecules of the same atomic formula have different structural arrangements: components of the molecule are the same but are arranged in a different configuration
Two broad classes:
* **Structural isomerism: **identical chemical formulae, but order of atomic bonds differs
* Stereoisomerism: same chemical constituents and bond structure but different three-dimensional configuration. Two forms: geometric, optical
Structural isomerism
Definition, examples
Identical chemical formulae, but order of atomic bonds differs. Depending on degree of structural similarity between the isomers, comparative pharmacological effects may be identical, or markedly different
Examples:
* Isoflurane and enflurance: both volatile anaesthetic agents
* Prendisolone and aldosterone: different activities - prednisolone has glucocorticoid and mineralocorticoid effects, aldosterone is predominantly mineralocorticoid
* Isoprenaline and methoxamine: different cardiovascular effects: isoprenaline acts via beta-adrenoceptors, methoxamine acts via alpha-adrenoceptors
* Dihydrocodine and dobutamine: very different pharmacological effects
Tautomerism
Definition, example in midazolam
Type of structural isomerism
= the dynamic interchange between two forms of a molcular structure, often precipitated by change in physical environment
E.g.: midazolam is ionised in solution at pH4, but at physiologicla pH 7.4, changes structure by forming a seven-membered unionised ring, rendering it lipid soluble: increased passage through BBB and speed of access to active sites in CNS.
Stereoisomerism
Definition, types
Stereoisomers have the same chemical constituents and bond structure, but a different 3D configuration
Two forms of stereoisomerism: Geometric and optical
Geometric:
* molecule has dissimilar groups attached to two atoms (often carbon) linked by either a double bond or in a ring structure.
* Free rotation of groups is restricted so groups may be either on same side of plane of double bond/ring (cis) or on opposite sides (trans)
Optical:
* have one or more chiral centres (chiral centre = a carbon atom or quartenary nitrogen surrounded by four different chemical groups).
* Single chiral centre -> R and S enantiomers ( two mirror image confirmations can occur which cannot be superimposed)
* >1 chiral centre -> diasteroisomers (multiple possible stereoisomers, not all mirror images of eachother so cannot be called enantiomers)
Geometrical isomerism
Definition, example
Type of **stereoisomerism. **
* Molecule has dissimilar groups attached to two atoms (often carbon) linked by a double bond or in a ring structure
* Free rotation of groups is limited: groups may be either on same side of plane of double bond/ring or on opposite sites
* Cis: on same side
* Trans: on opposite side
Example: bis-benzylisoquinolinium muscle relaxants e.g. mivacurium
* Two identical heterocyclic groups linked through an ester-containing carbon chain
* Each of the heterocyclic groups contains a planar ring with groups that may be arranged in either the cis- or trans- conformation
* Need to describe geometrical conformation, one for each heterocyclic group
* Therefore mivacurium has three geometric isomers: trans-trans (58%), cis-trans (36%), cis-cis (6%)
Enantiomers
Optical stereoisomers with one chiral centre (carbon or quarternary nitrogen surrounded by 4 different chemical groups)
Isomers are defined by the absolute spatial arrangement of the atoms of the four substituent groups directly attached to the chiral atom:
* Atom of lowest atomic number identified -> imagine this lying below the plane of the page
* Imagine other three atoms lying in the plane of the page, consider their atomic numbers
* ** R (rectus): atomic numbers descend ** clockwise fashion
* S (sinister): atomic numbers descend anticlockwise
* R and S are mirror images (cannot be superimposed), referred to as enantiomers
Examples of optical isomers with 1 chiral centre
- S- and R-warfarin
- S- and R-ketamine
- S- and R-etomidate (very different potencies)
- S- and R-isoflurane (similar potencies)
- S- and R-halothane
Do enantiomers have similar activity?
In general, 3D conformation of a drug determines its pharmacodynamic actions
* If drug acts via receptor: conformation matters, may be a marked difference between enantiomers
* If drug activity depends on a physiochemical property: would expect enantiomers to show similar activity
E.g.:
* S- and R-isoflurane have similar potency
* S- and R-etomidate have very different potency
Diasteroisomers
Difference from enantiomers, no. of possibilities, example
Type of optical stereoisomerism
>1 chiral centre present -> multiple possible stereoisomers, not all of which are mirror images of eachother, so cannot be called enantiomers.
Number of possible stereoisomers = number of chiral centres (n)^2
Note this is the maximum possible, however if molecule exhibits internal symmetry some of the possible configurations are duplicates: actual number of stereoisomers may be lower
Example: atracurium
* Four chiral centres (two carbon atoms, two quarternary nitrogen atoms) –> 4^2 i.e. 16 possible isomers
* However symmetric, so only 10 distinct 3D structures exist.
Drug preparations: Do all anaesthetic drugs have isomers? What different types of preparations of drugs with isomers exist?
- No isomers: Not all anaesthetic drugs have isomeric forms - if have neither a chiral centre nor structural features giving rise to geometric isomers. E.g.: Propofol, Sevoflurane, Dopamine
- Racemic mixtures: R and S enantiomers present in equal proportions
- Enantiopure preparations: pharmaceutical industry produces drug that has several isomers as a single isomer preparation, usually because one isomer is more active or lesss toxic
- Mixtures of multiple isomers: some drugs have multiple isometric forms, both geometrical and optical, due to their complex carbon structures. Medical preparations may contain all or only some isomers, in relative proportions determined by the synthetic process
Commonly used anaesthetic drugs that do not have isometric forms
Some anaesthetic drugs do not have a chiral centre or any geometric isomers
* Propofol
* Sevoflurane
* Dopamine
Racemic mixtures
Definition, preparation, examples
= equal amounts of R and S enantiomers of a chiral molecule or salt.
If drug has single chiral centre, different enantiomers are present in equal proportions:
* Isoflurane
* Ketamine
* Bupivacaine
* Warfarin
* Adrenaline
In nature, molecules with chiral centres often exist as single isomers as enzymes selectively produce just one. However if natural agents purified for use in medicine, this process often results in racemisation (both isomers present in pharmaceutical preparation) - for example, atropine
Note while mixture may contain equal amounts of the two isomers, contribution to pharmacodynamic and pharmacokinetic activity may be different.
Enantiopure preparations
Examples
A single isomer preparation of a drug with multiple isomers: usually because one isomer is more active or less toxic
* R-etomidate
* R-noradrenaline
* S-bupivacaine (levobupivacaine)
* S-ropivacaine
* S-ketamine
* S-medetomidine (dexmedetomidine)
* S-ketoprofen (dexketoprofen)
Drugs produced as mixtures of multiple isomers
Drugs with complex carbon structures, multiple isomeric forms, both geometric and optical.
Medical preparations may contain all or some of the possible isomers.
Relative proportions of isomers are determined by the sythetic process
* Vecuronium, pancuronium, atracurium
* Ephidrine
* Morphine, fentanyl, remifentanyl
