Structural Activity Relationships(SAR) of Benzodiazepines - Lorazepam, clonazepam

egpat
22 Dec 201910:50
EducationalLearning
32 Likes 10 Comments

TLDRThe video script offers an in-depth exploration of benzodiazepines, a class of psychoactive drugs. It begins with the common structure of benzodiazepines, highlighting the fused benzene ring and the seven-membered ring system with two nitrogen atoms, hence the name 'benzodiazepines'. The script delves into the structural activity relationships, emphasizing the importance of specific groups at different positions for optimal activity. For instance, a small alkyl group at the first position, a keto group at the second (except in chlordiazepoxide, which has a methylamino group that is later metabolized to a keto group), and a hydroxyl group at the third position for short-acting benzodiazepines. The fourth position typically features a double bond, while the fifth position often has a phenyl group, with substitutions at the ortho position enhancing activity. The sixth, eighth, and ninth positions should remain unsubstituted, and the seventh position requires an electron-withdrawing group, such as chlorine or a nitro group, for activity, with the latter being more potent. The video also discusses fused ring systems, such as the triazole and imidazole ring systems, which shift the positions of functional groups but maintain the essential features for benzodiazepine activity. This comprehensive overview underscores the intricate design and functionality of benzodiazepines, making it a valuable resource for those interested in the pharmacology of these drugs.

Takeaways
  • 🧬 The common structure of benzodiazepines includes a benzene ring fused with a seven-membered ring system containing two nitrogen atoms, hence the name 'benzo' and 'diazepine'.
  • πŸ”’ Benzodiazepines are numbered starting from the nitrogen at position 1, with the fused benzene ring not being numbered.
  • πŸƒ A small alkyl group, particularly a methyl group, at the first position is optimal for benzodiazepine activity.
  • βš™οΈ A keto group at the second position is essential for most benzodiazepines' activity, with exceptions like chlordiazepoxide, which has a methylamino group that is metabolized to a keto group.
  • πŸ’§ The presence of an OH group at the third position increases polarity and often results in short-acting benzodiazepines.
  • 🚫 The fourth position typically has a double bond, and its saturation reduces the activity of benzodiazepines.
  • 🌿 A phenyl group at the fifth position is crucial for benzodiazepine activity, with ortho substitution enhancing activity while para substitution decreases it.
  • ❌ Positions six, eight, and nine should not be substituted in the benzodiazepine structure.
  • ⚑ An electron-withdrawing group at the seventh position is necessary for benzodiazepine activity, with chlorine and nitro groups being common substitutions, where nitro increases potency due to higher electronegativity.
  • πŸ” Fused ring systems in benzodiazepines shift the numbering by one compared to the normal benzodiazepine structure, with unsaturation at the fifth position and an electron-withdrawing group at the eighth position being essential for activity.
  • πŸ’Š The structural activity relationships (SAR) of benzodiazepines dictate the potency and duration of action of the drugs, with specific substitutions at different positions affecting these properties.
Q & A
  • What is the basic structure of benzodiazepines?

    -The basic structure of benzodiazepines consists of a benzene ring fused with a seven-membered ring system containing two nitrogen atoms, hence the name 'benzo' for the benzene ring and 'diazepine' for the diazepines.

  • Why are benzodiazepines also referred to as 1,4-benzodiazepines?

    -Benzodiazepines are called 1,4-benzodiazepines because the nitrogen atoms are present at the first and fourth positions of the seven-membered ring.

  • What is the significance of having a small alkyl group at the first position in benzodiazepines?

    -A small alkyl group, particularly a methyl group, at the first position is optimal for the activity of benzodiazepines. Large alkyl groups or aromatic groups like phenyl decrease the activity.

  • Why is a keto group essential at the second position in benzodiazepines?

    -A keto group at the second position is essential for the activity of most benzodiazepines. It is involved in the receptor binding and contributes to the drug's efficacy.

  • How does the presence of a methylamino group at the second position in chlordiazepoxide allow it to be active?

    -Chlordiazepoxide, despite lacking a keto group at the second position, can still be active because it undergoes oxidative deamination, converting the methylamino group to a keto group, which is essential for activity.

  • What is the effect of having an OH group at the third position in benzodiazepines?

    -An OH group at the third position increases the polarity of the drug, which can lead to direct excretion in the urine and a short duration of action.

  • Why is the presence of a double bond at the fourth position in benzodiazepines important?

    -The double bond at the fourth position is crucial for the activity of benzodiazepines. Saturation of this double bond can lead to a loss of activity.

  • What is the role of a phenyl group at the fifth position in benzodiazepines?

    -A phenyl group at the fifth position is essential for activity. If the phenyl group is unsubstituted or has electron-withdrawing groups at ortho positions, it can increase the activity. However, para substitution decreases the activity.

  • Why should the sixth, eighth, and ninth positions in benzodiazepines not be substituted?

    -Substitution at the sixth, eighth, and ninth positions is not favorable as it can disrupt the receptor binding and potentially reduce the activity of the benzodiazepines.

  • What is the importance of an electron-withdrawing group at the seventh position in benzodiazepines?

    -An electron-withdrawing group at the seventh position is essential for the activity of benzodiazepines and also dictates the potency of the drug. Groups like chlorine or nitro increase the electronegativity at this position, enhancing the drug's potency.

  • How do fused ring systems in benzodiazepines affect the numbering and activity?

    -Fused ring systems, such as with a thiazole or imidazole ring, shift the numbering by one position compared to the normal benzodiazepine ring system. The positions that are essential for activity (unsaturation, phenyl group, and electron-withdrawing group) are shifted accordingly, maintaining their importance for the drug's efficacy.

  • What are some examples of benzodiazepines with fused ring systems?

    -Examples of benzodiazepines with fused ring systems include triazolam, which has a thiazole ring, and midazolam, which has an imidazole ring. These fused ring systems alter the chemical structure and potentially the pharmacological properties of the benzodiazepines.

Outlines
00:00
πŸ” Benzodiazepines Structure and Activity Relationships

This paragraph explains the common structure of benzodiazepines, characterized by a benzene ring fused with a seven-membered ring system containing two nitrogen atoms, hence the name 'benzodiazepines.' The numbering system for the benzene ring is introduced, and the significance of small alkyl groups, such as methyl, at the first position for optimal activity is discussed. The necessity of a keto group at the second position for most benzodiazepines is highlighted, with the exception of chlordiazepoxide, which has a methylamino group that is metabolized to a keto group. The impact of polar groups at the third position on the drug's duration of action is noted, with hydroxyl groups leading to short-acting benzodiazepines. The importance of a double bond at the fourth position and a phenyl group at the fifth position for activity is emphasized, with substitutions on the phenyl group affecting activity levels. The paragraph concludes with the importance of an electron-withdrawing group at the seventh position, which is essential for the activity and potency of benzodiazepines.

05:02
🧬 Fusion Ring Systems in Benzodiazepines

The second paragraph delves into fusion ring systems formed by combining benzodiazepines with other ring structures like thiophene or imidazole. The numbering system shifts with the fusion of rings, affecting the positions of the nitrogen atoms and the subsequent positions in the benzodiazepine structure. The paragraph explains that the unsaturation typically at the fourth position in benzodiazepines moves to the fifth position in fused ring systems. Similarly, the electron-withdrawing group that is usually at the seventh position moves to the eighth. The necessity of these structural features for the activity of the fused ring systems is emphasized. Examples of drugs with fused ring systems, such as triazolam and midazolam, are provided, noting differences in their structures and substitutions that affect activity and potency.

10:04
πŸ›‘οΈ Structural Requirements for Benzodiazepines Activity

The final paragraph summarizes the structural requirements for benzodiazepines to be active. It reiterates the importance of a simple alkyl group at the first position, a keto group at the second, and the avoidance of substitution at the third position to prevent polarity and ensure a short duration of action. The presence of a double bond at the fourth position and a phenyl group at the fifth, with specific substitutions affecting activity, is again highlighted. The paragraph stresses that positions six, eight, and nine should not be substituted, while an electron-withdrawing group at the seventh position is essential for activity, with the type of group influencing the potency of the benzodiazepine.

Mindmap
Keywords
πŸ’‘Benzodiazepines
Benzodiazepines are a class of psychoactive drugs that are commonly used for their sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties. They are characterized by a common chemical structure which includes a benzene ring fused to a seven-membered ring system containing two nitrogen atoms. In the video, the structure and activity of benzodiazepines are discussed in detail, highlighting their importance in the field of pharmaceuticals.
πŸ’‘Structural Activity Relationships (SAR)
Structural Activity Relationships (SAR) is a concept in pharmacology that describes the relationship between the molecular structure of a compound and its biological activity. The video focuses on SAR of benzodiazepines, explaining how different groups at various positions on the benzodiazepine structure affect the potency and activity of the drug. This is crucial for understanding how modifications to the structure can lead to changes in the drug's effectiveness.
πŸ’‘Alkyl Group
An alkyl group is a chemical group derived from an alkane by removing a hydrogen atom. The video mentions that a small alkyl group, particularly a methyl group, is optimal for the activity of benzodiazepines. This is exemplified by drugs such as diazepam and alprazolam, which contain a methyl group at the first position in their structure.
πŸ’‘Keto Group
A keto group, also known as a ketone group, is a functional group with the structure C=O. The script emphasizes that a keto group at the second position is essential for the activity of benzodiazepines, with the exception of chlordiazepoxide, which has a methylamino group that can be oxidized to a keto group.
πŸ’‘Polarity
Polarity in chemistry refers to the distribution of charge and the presence of polar bonds within a molecule. The video explains that if a hydroxyl (OH) group is present at the third position of a benzodiazepine, it increases the molecule's polarity, which can lead to direct excretion in urine and a short duration of action for the drug.
πŸ’‘Double Bond
A double bond is a covalent bond between two atoms involving four bonding electrons instead of the usual two. The script indicates that a double bond at the fourth position of benzodiazepines is crucial for their activity, and its saturation can reduce the drug's effectiveness.
πŸ’‘Phenyl Group
A phenyl group is a hydrocarbon group with the formula C6H5-. It is an essential part of the benzodiazepine structure, typically attached at the fifth position. The video discusses how the presence of a phenyl group, especially when substituted with electron-withdrawing groups at ortho positions, can increase the activity of benzodiazepines.
πŸ’‘Electron-Withdrawing Group
An electron-withdrawing group is a substituent that draws electron density away from the rest of the molecule. The video highlights the importance of an electron-withdrawing group, such as a chlorine or nitro group, at the seventh position for the activity and potency of benzodiazepines. The greater the electronegativity of the group, the more potent the benzodiazepine is likely to be.
πŸ’‘Fused Ring Systems
Fused ring systems in chemistry refer to rings that share two or more adjacent atoms. The video explains that benzodiazepines can have fused ring systems, such as with a thiazole or imidazole ring, which alters the numbering and positions of functional groups on the benzodiazepine structure. This fusion affects the drug's activity and properties.
πŸ’‘Metabolite
A metabolite is a substance produced during or as a result of metabolism. The script mentions 'demeclocycline' (likely a mispronunciation of 'diazepam') as an important metabolite of chlordiazepoxide, which has a keto group at the second position, indicating its role in the drug's activity after metabolic conversion.
πŸ’‘Electronegativity
Electronegativity is a measure of the tendency of an atom to attract a bonding pair of electrons. The video uses the concept of electronegativity to explain the varying potencies of benzodiazepines based on the electron-withdrawing group at the seventh position, with nitro groups being more electronegative and thus leading to more potent drugs.
Highlights

Benzodiazepines have a common structure consisting of a benzene ring fused with a seven membered ring system containing two nitrogens.

Benzodiazepines are named based on the presence of the benzene ring (benzo) and the seven membered ring with nitrogens (diazepine).

Numbering of benzodiazepines starts from the nitrogen atoms at positions 1 and 4, hence they are also called 1,4-benzodiazepines.

A small alkyl group, especially a methyl group, at the first position is optimal for benzodiazepine activity.

A keto group at the second position is essential for most benzodiazepines, with chlordiazepoxide being an exception.

Chlordiazepoxide has a methylamino group at the second position, which gets oxidized to a keto group, forming the active metabolite demetriomide.

An hydroxyl (OH) group at the third position increases polarity, leading to short duration of action for benzodiazepines.

Benzodiazepines with a double bond at the fourth position have reduced activity compared to those without.

A phenyl group at the fifth position is crucial for benzodiazepine activity, with ortho substitution enhancing it.

Para substitution on the phenyl group at the fifth position decreases benzodiazepine activity.

Positions 6, 8, and 9 should not be substituted in benzodiazepines.

An electron-withdrawing group, typically a chlorine or nitro group, at the seventh position is essential for benzodiazepine activity and potency.

Fused ring systems, formed by fusing the benzene ring with a five or six membered ring, have a shifted numbering compared to typical benzodiazepines.

In fused ring systems, unsaturation at the fifth position, a phenyl group at the sixth, and an electron-withdrawing group at the eighth are essential for activity.

Famous fused benzodiazepines include alprazolam and triazolam.

The structure-activity relationships of benzodiazepines are crucial for understanding their activity, potency, and duration of action.

Transcripts
Rate This

5.0 / 5 (0 votes)

Thanks for rating: