Structure-Activity-Relationships (SAR - PowerPoint PPT Presentation .. Metabolic Activation and Idiosycratic Drug Toxicity: By Avoiding Structural Alerts, Do We. Structure activity relationship in drug action Presented by- Dr Suyash Bharat PG JR 1ST PHARMACOLOGY, GMC Haldwani (Nanital). Drug Design: Functional groups / Pharmacological Activity. Structure - Mechanism of SAR: Structure Activity Relationships. Acetylcholine agonists: Small.
However, the selection of the system for a particular analogue may depend on the objective of the alteration. The latter means that small aromatic systems such as benzene and five membered heterocyclic systems are preferred to larger systems.
Structure-Activity-Relationships (SAR - PowerPoint PPT Presentation
Furthermore, heterocyclic aromatic systems will also introduce extra functional groups into the structure, which could also affect the potency and activity of the analogue. For example, the replacement of N-dimethyl group of chlorpromazine by an N-methylpiperazine group produces an analogue prochlorperazine with increased antiemetic potency but reduced neuroleptic activity.
It has been suggested that this change in activity could be due to the presence of extra tertiary-amine group 18 Structure- Activity Relationships SAR Changing size and shape Introduction or Removal of Ring System 19 Structure- Activity Relationships SAR Changing size and shape Introduction or Removal of a Ring System The incorporation of a ring systems, especially larger systems into a structure of a lead can be used to produce analogues that are resistant to enzymatic attack by sterically hindering the access of the enzyme to the relevant functional group.
Furthermore, they also tend to exhibit unwanted side effects. However, the structures of many of these compounds contain several ring systems. In these cases, one approach to designing analogues of these compounds centres around determining the pharmacophore and removing any surplus ring structures. It is hoped that this will also result in the loss of any unwanted side effects. For example, the introduction of a new substituent may cause significant changes in lipophilicity that affect transport of the analogue through membranes and the various fluids found in the body.
It would also change the shape, which could result in conformational restrictions that affect the binding to the target site. In addition, the presence of a new group may introduce a new metabolic pathway for the analogue. These changes will in turn affect the pharmacodynamic properties of the analogue.
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For example, they could result in an analogue with either increased or decreased potency, duration of action, metabolic stability and unwanted side effects. However, it is possible to generalize about the effect of introducing a new substituent group into a structure but there will be numerous exceptions to the predictions.
P values for Toluene,PropionamideN-methlurea For example, the ortho-methyl analogue of diphenhydramine exhibits no antihistaminic activity. Harmes and colleagues suggest that this could be due to the ortho-methyl restricting rotation about C-O bond of the side chain.
This prevents the molecule from adopting the conformation necessary for antihistaminic activity. It is interesting to note that the para-methyl analogue is 3. A number of methyl transfers have been associated with carcinogenic action. For example the action of the agricultural fungicide nabamis due to it being metabolised to the deactive diisothiocyanate. N-Methylation of nabam yeilds and analogue that is inactive because it cannot be metabolised to the diisothiocyanate.
For example, mono and di ortho-methylation with respect to the phenolic hydroxy group of paracetamol produce analogues with reduced hepatotoxity. It is believed that this reduction is due to the methyl groups preventing metabolic hydroxylation of these ortho positions. Consequently, halogen atoms are used to improve the penetration of lipid membranes. However, there is an undesirable tendency for halogenated drugs to accumulate in the lipid tissues. The chemical reactivity of halogen atoms depends on both their point of attachment to the lead and the nature of the halogen.
Aromatic halogen groups are far less reactive than aliphatic halogen groups, which can exhibit considerable chemical reactivity. For aliphatic carbon-halogen bonds C-F bond is the strongest and usually less chemically reactive than aliphatic C-H bonds. They are usually more chemically reactive than aliphatic C-H bonds. Consequently, the most popular halogen substitutions are the less reactive aromatic fluorine and chlorine groups.
However, the presence of electron-withdrawing ring substituents may increase their reactivity to unacceptable level. Trifluorocarbon groups -CF3 are sometimes used to replace chlorine because these groups are of a similar size.
These substitutions avoid introducing a very reactive centre and hence possible site for unwanted side reactions into the analogue. For example, the introduction of the more reactive bromo group can cause the drug to act as an alkylating agent. It is believed that the bulky ortho chlorine groups impose a conformation restriction on the structure of Clonidine, which probably accounts for its increased activity.
It also provides a new centre for hydrogen bonding which could influence the binding of the analogue to its target site. For example, the orthohydroxylated minaprine analogue binds more effectively to M1- muscarinic receptors than many of its non-hydroxylated analogues. The introduction of hydroxy group also introduces a centre that, in the case of phenolic groups, could act as a bacteriocide whereas alcohols have narcotic properties.
However, the presence of hydroxy groups opens a new metabolic pathway that can either act as a detoxification route or prevent the drugs from reaching its target. All these basic groups can form salts in biological media. Consequently, incorporation of these basic groups into the structure of lead will produce analogues that have a lower lipophilicity but an increased water solubility.
This means that the more basic an analogue, the more likely it will form salts and the less likely it will be transported through a lipid membrane. However, a number of drugs with basic groups owe their activity to salt formation and the enhanced binding that occurs due to the ionic bonding between the drug and the target. For example, it is believed that many local anaesthetics are transported to their site of action in the form of their free bases but are converted to their salts which bind to the appropriate receptor sites.
The incorporation of aromatic amines into the structure of a lead is usually avoided because aromatic amines are often very toxic and carcinogenic.
If it is acidic pH the drug molecule should be acidic in nature to exist as unionised form and pKa required is below 8. In basic environment it should be basic in nature to exist as unionised form, pKa required is above 8.
Water solubility For hydrophobic drugs like Griseofulvin and Spiranolactone dissolution step is the rate limiting step. For hydrophilic drugs like Chromalin sodium permeation is the rate limiting step.
It means if two drugs having same absorption rate constant are present then the drug with greater solubility will have maximum absorption. Drugs with possibility of more hydrogen bond formation will have more solubility. If the drug is more hydrophobic it will have high p value and it can cross biological membranes easily. Partition co- effecient of a drug can be determined by its distribution in an octanol-water mixture.
Low lipophilicity unionized form - low absorption logP - P: The differences in biologic activity between optical isomers depend on their ability to react selectively at an asymmetric center in the biologic system. It is easily seen from the diagram that of the two enantiomorphs, only one A has the correct orientation for all three groups to fit at their respective sites.
Ephedrine and pseudo ephedrine are the diastereomers Among the optical isomers of ephedrine and pseudo ephedrine only D - ephedrine can significantly block the adrenergic receptors there by lowering blood pressure.
Bioisosteres Substituents or groups with chemical or physical similarities that produce similar biological properties.
The electronic effects of various substituents will clearly have an effect on a drug's ionization or polarity.
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This in turn may have an effect on how easily a drug can pass through cell membranes or how strongly it can bind to a receptor. After drug reaching its target site distribution of electrons in its structure will control the type of bond between them.
These are the different physico chemical properties of a drug molecule that are required to elicit pharmacological action.