Lecture 19 - Histamine and Histamine Receptors

structural evaluation of histamine

1. molecule consists of an imidazole ring and ethylamino side chain

2. CH2 groups near amino group are designated alpha and beta (alpha closest to NH2)

3. pKas are 5.8 (imidazole) and 9.40 (amine)

4. exists primarily in ionized form at physiological pH

biosynthesis of histamine

L-histidine (substrate) —> histamine via histidine decarboxylase (enzyme) and pyridoxal phosphate (co-factor)

how is histamine stored

as an inert, ionic complex

primary site of histamine storage

granules of mast cells

secondary sites of histamine storage

o Skin and Lungs (bronchial tissue) – highest concentration of mast cells/histamine

o Mucosal layer of GI tract

o Heart (cardiomyocytes)

o CNS – histamine biosynthesized locall

why is histamine released from cell

antibodies —> PLC activation —> IP3 + DAG —> intracellular calcium increase

pathway I of metabolism of histamine

1. Oxidative deamination to the aldehyde (oxidative deamination by diamine oxidase)

2. Oxidation of the aldehyde to the carboxylic acid (oxidation)

3. Ribosylation (similar to glucuronidation) of imidazole ring (non-basic nitrogen)

pathway II of metabolism of histamine

1. Methylation of imidazole non-basic nitrogen

2. Oxidative deamination to the aldehyde by MAO-B or diamine oxidase

3. Oxidation of the aldehyde to the carboxylic acid

ways histamine action can be terminated

• cellular uptake (major)

• receptor desensitization (secondary)

• metabolism (minor)

minor mechanism for drugs that reduce histamine’s effects

Inhibit release of histamine from storage sites (few drugs belong to this class) - preventive

major mechanism for drugs that reduce histamine’s effects

Block the histamine receptors with antagonists (bulk of the drugs are in this category)

first generation H1 antagonist purpose

treatment of allergic responses such as hay fever, rhinitis, urticaria, and food allergies

issue with gen 1 antihistamines and receptors

gen 1 antihistamines can act on numerous receptor types, not just H1. this can cause many unintended side effects

adverse central effects of gen 1 antihistamines

• sedation

• drowsiness

• decreased cognition

• somnolence

adverse peripheral effects of gen 1 antihistamines

• blurred vision

• dry mouth

• urinary retention

• constipation

1st gen H1 antagonist SAR

1. two aromatic rings —> steric bulk required for antagonist

2. X group —> defines class

3. spacer linking bulk to basic amine

4. basic, tertiary aliphatic amine —> ionized so molecule can bind

advantages of 2nd gen over 1st gen antihistamines

• 2nd gen has higher affinity for H1 receptor, prolonging duration of action

• 2nd gen has high H1 selectivity due to polar group → decreased binding to other receptor types

• 2nd gen has low potential to cause CNS effects due to polar group AND lower affinity for central H1 receptors

2nd gen H1 antagonist SAR

1. two aromatic rings —> steric bulk required for antagonist

2. X group —> defines class

3. Y group in ring —> defines ring structure

4. basic amine —> ionized so molecule can bind

5. polar group —> increases H1 receptor selectivity

(X and Y directly connected)

gen 1 vs gen 2 antihistamine SAR

polar group after nitrogen, and sometimes 2 nitrogens in 2nd gen

inhibitors of histamine release SAR

1. Chromone (benzopyrone) —> blue

2. Carboxylate anions (2) —> black

chemical classes of gen 1 antihistamines

1. ethylenediamine

2. phenothiazine

3. aminoalkyl ether / ethanolamine

4. propylamine

5. piperazine

6. Dibenzocycloheptanes/heptenes

Ethylenediamine class SAR

1. two aromatic rings —> steric bulk required for antagonist

2. X group —> nitrogen

3. spacer linking bulk to basic amine

4. basic, tertiary aliphatic amine —> ionized so molecule can bind

(“ethyl” spacer, “di-amine” 2 nitrogens)

Phenothiazine Class SAR

1. two aromatic rings LINKED with sulfur—> steric bulk required for antagonist

2. X group —> nitrogen

3. spacer linking bulk to basic amine

4. basic, tertiary aliphatic amine —> ionized so molecule can bind

(pheno = phenyls, thi = sulfur, az = nitrogen, ine = 6 membered ring)

Aminoalkyl Ether Class (or Ethanolamine Class) SAR

1. two aromatic rings —> steric bulk required for antagonist

2. X group —> ether (C-O)

3. spacer linking bulk to basic amine

4. basic, tertiary aliphatic amine —> ionized so molecule can bind

(ethanol = ethanol spacer, amine = amine)

Propylamine Class SAR

1. two aromatic rings —> steric bulk required for antagonist

2. X group —> sp3 carbon (1 or 0 hydrogens OK)

3. spacer linking bulk to basic amine

4. basic, tertiary aliphatic amine —> ionized so molecule can bind

Piperazine Class SAR

1. two aromatic rings —> steric bulk required for antagonist

2. X group —> piperazine ring system (seems like 2nd gen, but no polar group attached)

3. spacer linking bulk to basic amine

4. basic, tertiary aliphatic amine —> ionized so molecule can bind

5. additional bulk attached to piperazine —> increase antagonist action

Dibenzocycloheptanes/heptenes SAR

1. two aromatic rings LINKED with 7 membered ring—> steric bulk required for antagonist

2. X group —> sp3 carbon (no hydrogens)

3. spacer linking bulk to basic amine

4. basic, tertiary aliphatic amine —> ionized so molecule can bind