Ulcers - Vino

Histidine

Histamine

1st gen H2 antagonist

Which one has a higher affinity, Histidine or Histamine?

Histidine

Histamine is synthesized by which enzyme?

decarboxylase

Where is decarboxylase located?

mast cells, basophil granulocytes

"Chemical messenger"
Communication in multicellular organisms

Histamine

Histamine in TRANS conformation prefer which type of receptors?

H1 and H2

Histamine in GAUCHE conformation prefer which type of receptors?

H3

Histamine Trans conformation

Histamine GAUCHE conformation

Addition of other alkyl substitution on the histamine generally do what to the compound for H1 and H2 Receptors?

Decrease potency

Nitrogen substitution in Histamine Receptors does what?

decrease activity

When there is a substitution at position 4 of the H Antagonist how does it affect the Nt-H tautomer?

reduce activity by 70%

Cl- substitution on the Nt-H tautomer will do what to its activity?

reduce activity to 12%

What structure within Histamine is very important for receptor type selectivity?

tautomerism of the imidazole ring

Histamine prefers which form of tautomer?

Nt-H tautomer

Is Nt-H tautomer active or inactive form?

active

Histamine is active for which receptors?

H1 and H2, but idea was to increase selectivity so it will only work on H2 Receptors

Burimamide

1st gen H2 antagonist

Methiamide

1st gen H2 Antagonist

Which form does Burimamide favor? Why?

Nπ-H tautomer because it has a electron donating effect leading to its low potency

Which form does Methiamide prefer?

Nt-H tuatomer
because its electron withdrawing property allows it to become more potent

How does Methiamide become more selective?

With the addition of the methyl group at position 4 on the imidazole ring

Burimamide is what receptor?

Full H2 atagonist receptor

Name all the 1st gen H2 Antagonist drugs

Histamine
Burimamide
Methiamide

Name all the 2nd H2 Receptor Antihistamines

Cimetidine
Ranitidine
Nizatidine
Famotidine

Cimetidine (Tagamet)

2nd gen H2 Receptor Antihistamine

Ranitidine (Zantac)

2nd gen H2 Receptor Antihistamine

Nizatidine (Axid)

2nd gen H2 Receptor Antihistamine

Famotidine (Pepcid)

2nd gen H2 Receptor Antihistamine

Which drug has short action duration, and low selectivity (antiandrogenic)?

What are 3 characteristics 2nd gen H2 Receptor Antihistamines have in common?

- short 1/2 life
-1st Pass metabolism

Which 2nd gen H2 Receptor Antihistamine has the largests bioavailability?

What conformation does Famotidine prefer?

Nt-H tautomer

2nd gen H2 Receptor Antagonists SAR

- Nt-H tautomer is preferable for max H2-antagonistic activity
-for separation of the ring and nitrogen group equivalent of 4-carbon chain is necessary
- isosteric thioether link is good
-the terminal N-containing functionality should be polar, nonbasic substituent

Which 2nd gen H2 Receptor Antagonist Antihistamine Receptor is LEAST potent?

Which 2nd gen H2 Receptor Antagonist Antihistamine Receptor is MOST potent?

Omeprazole

PPI

Esomeprazole

PPI

Rabeprazole

PPI

Pantoprazole

PPI

Which PPI interacts with CYP2C19, CYP2A4, CYPSC19 O-

Which PPI interacts with CYP3A4 only?

Which PPI interacts with CYP2C19, and CYPSA4?

Rabeprazole and Esomeprazole

Which PPI is the R isoform (metabolizes faster)?

Which PPI is the S isoform (metabolizes slower)?

Which PPI has the shortess 1/2 life?

This S isoform PP1 has a longer 1/2 life than omeprazole

Which PPI has the longest 1/2 life?

PMSBs (Pyridinylmethysulfinyl benzimidazoles) SAR

- 3 structural elements: pyriding ring, benzimidaole ring system, and the sulfinyl linking chain
\-

Which PPI has highest bioavailability?

Which PPI has lowest bioavailability?

PPI inhibitor general structure

Tenatoprazole

position 4 with N-

Which PPI has 2nd highest bioavailability?

SAR of PPI

3 structural elements: the pyriding ring, the benzimidazole ring system and the sulfinyl linking chain· Replacement of SOCH2 or extending the link by various groups leads to loss of activity· In pyridine ring system degree of nucleophilicity (rather than basicity) of N reflects the ease of intermediates formation, substitution at 6'-position results in loss of activity as disfavoring steric interaction· Substitutions in benzimidazole ring does not change the activity to a great extent, introduction of electron withdrawing substituents, like 5'-NO2, 5'-MeSO, 5'-CF3, leads to decreased enzyme inhibition

When replacing the SOCH2 or extending the link by various group how does this affect the PPI?

loses activity

Substitution at the 6' position of the PPI does what to its function?

loss of activity as its disfavoring the steric interaction

Name 3 subtituents that introduce electron-withdrawing to PPI

- 5'-NO
- 5'-MeSO
- 5'-CF3

T/F Substitution in benzimidazole affects its activity.

True

Prostaglandin E1

Mistoprostol

Sulcralfate

Bismuth

This drug can form a cross-linkage

This drug can create a sulfate-aluminum complex

Introduction of electron withdrawing substituents does what to the PPI's activity?

decrease enzyme inhibition

Histidine

Histamine

1st gen H2 antagonist

Which one has a higher affinity, Histidine or Histamine?

Histidine

Histamine is synthesized by which enzyme?

decarboxylase

Where is decarboxylase located?

mast cells, basophil granulocytes

"Chemical messenger"
Communication in multicellular organisms

Histamine

Histamine in TRANS conformation prefer which type of receptors?

H1 and H2

Histamine in GAUCHE conformation prefer which type of receptors?

H3

Histamine Trans conformation

Histamine GAUCHE conformation

Addition of other alkyl substitution on the histamine generally do what to the compound for H1 and H2 Receptors?

Decrease potency

Nitrogen substitution in Histamine Receptors does what?

decrease activity

When there is a substitution at position 4 of the H Antagonist how does it affect the Nt-H tautomer?

reduce activity by 70%

Cl- substitution on the Nt-H tautomer will do what to its activity?

reduce activity to 12%

What structure within Histamine is very important for receptor type selectivity?

tautomerism of the imidazole ring

Histamine prefers which form of tautomer?

Nt-H tautomer

Is Nt-H tautomer active or inactive form?

active

Histamine is active for which receptors?

H1 and H2, but idea was to increase selectivity so it will only work on H2 Receptors

Burimamide

1st gen H2 antagonist

Methiamide

1st gen H2 Antagonist

Which form does Burimamide favor? Why?

Nπ-H tautomer because it has a electron donating effect leading to its low potency

Which form does Methiamide prefer?

Nt-H tuatomer
because its electron withdrawing property allows it to become more potent

How does Methiamide become more selective?

With the addition of the methyl group at position 4 on the imidazole ring

Burimamide is what receptor?

Full H2 atagonist receptor

Name all the 1st gen H2 Antagonist drugs

Histamine
Burimamide
Methiamide

Name all the 2nd H2 Receptor Antihistamines

Cimetidine
Ranitidine
Nizatidine
Famotidine

Cimetidine (Tagamet)

2nd gen H2 Receptor Antihistamine

Ranitidine (Zantac)

2nd gen H2 Receptor Antihistamine

Nizatidine (Axid)

2nd gen H2 Receptor Antihistamine

Famotidine (Pepcid)

2nd gen H2 Receptor Antihistamine

Which drug has short action duration, and low selectivity (antiandrogenic)?

What are 3 characteristics 2nd gen H2 Receptor Antihistamines have in common?

- short 1/2 life
-1st Pass metabolism

Which 2nd gen H2 Receptor Antihistamine has the largests bioavailability?