Med Chem Lecture 14 Spring

Front 1

Histamine (2-(1H-imidazol-4-yl)ethanamine) is a small molecule containing an ______ ring

Back 1

imidazole

Front 2

The imidazole ring exists as two _____ where the hydrogen is on the ___ nitrogen or on the __ nitrogen

Back 2

tautomers

The imidazole ring exists as two tautomers where the hydrogen is on the π nitrogen or on the τ nitrogen.

Front 3

In aqueous solution, the ___– hydrogen form of histamine predominates, but as a solid the ____– hydrogen form is found

Back 3

In aqueous solution, the τ – hydrogen form of histamine predominates, but as a solid the π – hydrogen form is found

Front 4

Histamine

Changes in tautomeric composition occur with changes in _______ of the imidazole ring.

Back 4

5-substitution

Front 5

The 5-substituents that provide the lower proportions of the τtautomer also have decreased _____ ____

Back 5

agonist potency

Front 6

Histamine

The pKa values for the nitrogens in histamine are ___for the imidazole and ____ for the primary amine.

Back 6

The pKa values for the nitrogens in histamine are 5.8 for the imidazole and 9.4 for the primary amine.

Front 7

Histamine
The pKa values for the nitrogens in histamine are 5.8 for the imidazole and 9.4 for the primary amine. At physiological pH it exists as a ___ monocation and ____ dication forms.

Back 7

a 96% monocation and 3% dication forms

Front 8

Histamine

If the imidazole ring is replaced by a small, less basic heterocyclic ring there will still be ____ activity

Back 8

agonist

Front 9

histamine

If the imidazole ring is replaced by a small, less basic heterocyclic ring there will still be agonist activity, suggesting that a protonated heterocyclic ring (the dicationic form) is not required for ___-___ interaction

Back 9

agonist-receptor interaction.

Front 10

Histamine is one of the many mediators involved in ___ ___ responses and it has an important role in regulating the secretion of

Back 10

allergic inflammatory

gastric acid

Front 11

What histamine treates allergic inflammatory disorders

What treats gastric hypersecretory disorder

Back 11

treatment of allergic inflammatory disorders (H1 antihistamines) and in the treatment of gastric hypersecretory disorders (H2 antihistamines).

Front 12

Histamine is synthesized in the ___ _____ of ____ cells and b_____ by enzymatic _____of ____

Back 12

Histamine is synthesized in the Golgi apparatus of mast cells and basophils by enzymatic decarboxylationof histidine

Front 13

Histamine is synthesized in the Golgi apparatus of mast cells and basophils by enzymatic decarboxylationof histidine. This conversion is catalyzed by
_____, with ___ __ serving as a cofactor

Back 13

This conversion is catalyzed by
L-histidinedecarboxylase,withpyridoxal phosphate serving as a cofactor.

Front 14

Allergens cause what cells to produce what, associated with what?

Back 14

Allergens cause white blood cells to produce antibodies which associate with mast cells.

Front 15

What do antigens interact with?

Back 15

Antigens interact with immunoglobulin and mast cell FcεRI receptors.

Front 16

Antigens interact with immunoglobulin and mast cell FcεRI receptors. The mast cells are then sensitized to allergens and release preformed ____ when ___

Back 16

preformed histamine when activated

Front 17

What is Kellen?

Back 17

a pharmocologically active natural product isolated from a plant used by ancient Egyptians for the treatment of bronchial spasms.

Front 18

What did initial research of Kellen lead to the development of?

What do thy both inhibit?

Back 18

. Initial research led to the development of cromolynand nedocromil, which both inhibit the degranulation of mast cells

Front 19

What is degranulation of mast cells?

Back 19

the biochemical process by which mast cells release histamine and other cell activating chemicals in response to immonoglubulin

Front 20

Most H1 antihistamines are __ ___ rather than __ ___

Back 20

inverse agonists rather than neutral antagonists.

Front 21

Like other histamine receptors, H1 receptors have constitutive _ __-___ activity in the absence of the __ ___ that results in the activation of the ___-____ ____ pathways

Back 21

G protein–coupled activity in the absence of the agonist histamine that results inactivation of second-messenger signaling pathways.

Front 22

. Inverse agonists bind to the ____ _____ of the receptor, shifting the equilibrium toward the ____ state.

Back 22

. Inverse agonists bind to the inactive conformation of the receptor, shifting the equilibrium toward the inactive state.

Front 23

Neutral antagonists interact with?

Back 23

both conformations of the receptor.

Front 24

The first-generation H1 antihistamines are useful and effective in the treatment of what?

Back 24

of allergic responses (e.g., hayfever, rhinitis, urticaria, and food allergy)

Front 25

first-generation H1 antihistamines also have effects at what receptors?

Back 25

cholinergic, adrenergic, dopaminergic, and serotonergic receptors.

Front 26

first-generation H1 antihistamines has what central side effects?

Back 26

Central side effects include sedation, drowsiness, decreased cognitive ability, and somnolence

Front 27

first-generation H1 antihistamines has what peripheral side effects?

Back 27

Peripheral side effects associated with cholinergic blockade include blurred vision, dry mouth,urinary retention, and others.

Front 28

Of all the first-generation H1 antihistamines side effects, what is the most common?

Back 28

CNS depression is the most common

Front 29

the first-generation H1 antihistamines side effects can also be used as what kind of otc?

Back 29

over-the-counter (OTC) sleep aids.

Front 30

In order to minimize the CNS depressant/anticholinergic effects and retain peripheral antihistaminic effects of these drugs, the ___-____ __ ______ were developed?

Back 30

second-generation H1 antihistamines were developed.

Front 31

Structural classes of H1 antihistamines can be represented by a general structure consisting of what?

Back 31

two aromatic (Ar) groups linked through a short chain to a tertiary aliphatic amine.

Front 32

First Generation (Sedating) H1 Antihistamines


Structural classes of H1 antihistamines can be represented by a general structure of two aromatic (Ar) groups linked through a short chain to a tertiary aliphatic amine. These substituents are attached to the X group, which is a __ atom in the ___

Back 32

a nitrogen atom in the ethylenediamines,

Front 33

First Generation (Sedating) H1 Antihistamines

These substituents are attached to the X group, which is a nitrogen atom in the ethylenediamines, a carbon attached to an ___ ___ atom in the ____ ___ series, or only a carbon atom in the ___ ___

Back 33

ethanolamine ether series, or only a carbon atom in the alkyl amines.

Front 34

First Generation (Sedating) H1 Antihistamines

The spacer usually is what length? IT may be in a way what? It may be __ ___ or ___

Back 34

is two or three carbons in length, and it may be in a ring (like the piperazineantihistamines), may be branched, and may be saturated or unsaturated.

Front 35

First Generation (Sedating) H1 Antihistamines

The R groups attached to the aliphatic amine usually are simple what?

Back 35

are simple alkyl groups, generally methyl.

Front 36

First Generation (Sedating) H1 Antihistamines

The forerunner of all modern antihistamines was ___, an ______ antihistamine.

Back 36

The forerunner of all modern antihistamines was Antergan, an ethylenediamine antihistamine.

Front 37

First Generation (Sedating) H1 Antihistamines

The forerunner of all modern antihistamines was Antergan, an ethylenediamineantihistamine. This compound had significant toxicities associated with the ___ chemical structure

Back 37

aniline

Front 38

First Generation (Sedating) H1 Antihistamines

The prototype of the ethanolamine ether antihistamine is ____

Back 38

diphenhydramine

Front 39

First Generation (Sedating) H1 Antihistamines

What else is widely used?

Back 39

. Doxylamineis still widely used as well.

Front 40

First Generation (Sedating) H1 Antihistamines

A third class of analogues is one in which a carbon atom replaces the heteroatom spacer in the general structure the ___ __

Back 40

alkyl amines

Front 41

First Generation (Sedating) H1 Antihistamines

A third class of analogues is one in which a carbon atom replaces the heteroatom spacer in the general structure the alkyl amines. Examples are what 3?

Back 41

pheniramine, chlorpheniramine, and brompheniramine.

Front 42

First Generation (Sedating) H1 Antihistamines

The ring halogen–substituted compounds are widely used for what?

Back 42

OTC antihistamines for mild seasonal allergies.

Front 43

First Generation (Sedating) H1 Antihistamines

These agents are characterized by what?

Back 43

These agents are characterized by a long duration of antihistaminic action and by a decreased incidence of central sedative side effects compared to the ethylenediamines and ethanolamine ether series.

Front 44

First Generation (Sedating) H1 Antihistamines

Members of the piperazineclass of agents are structurally related to both the __ __ and the __ ___ of ____

Back 44

ethylenediamines and the benzhydryl ethers of ethanolamines

Front 45

First Generation (Sedating) H1 Antihistamines

Members of the piperazineclass of agents are structurally related to both the ethylenediamines and the benzhydryl ethers of ethanolamines. Their structures include what?

Back 45

the 2 carbon separation between nitrogen atoms, which is incorporated into a piperazinering.

Front 46

Piperazine class of agents primary use of these compounds remains treatment of what?

Back 46

motion sickness and vertigo and suppression of nausea and vomiting.

Front 47

Hydroxyzineis largely used in treatment of what?

Back 47

itch

Front 48

Hydroxyzine acid metabolite is what?

Back 48

cetirizine

Front 49

Hydroxyzineis largely used in treatment of pruritis (itch). Its acid metabolite, cetirizine, which is formed from what?

Back 49

oxidation of the terminal primary alcohol to the corresponding carboxylic acid, usually is classified with the second-generation, nonsedating antihistamines.

Front 50

The amphoteric nature of cetirizine, having both the tertiary aliphatic ___ and __ __ appears to be associated with __ sedative side effects

Back 50

amine (basic)and carboxylic acid (acidic) functional groups, appears to be associated with decreased, but not absent, sedative side effects.

Front 51

Second Generation (Nonsedating) H1 Antihistamines vary in what?

Back 51

They vary widely in structure

Front 52

Second Generation (Nonsedating) H1 Antihistamines having effects principally in where?

Back 52

peripheray

Front 53

Second Generation (Nonsedating) H1 Antihistamines do not penetrate what? because why? What kind of substrates are they?

Back 53

They do not penetrate the blood-brain barrier significantly because of their amphoteric nature (most are zwitterionic at physiological pH) and the fact that they are P-gp substrates

Front 54

Second Generation (Nonsedating) H1 Antihistamines have what kind of duration of action and are usually adminstered when?

Back 54

These drugs have an extended duration of action and are usually administered once daily.

Front 55

Terfenadine was once used, but is no longer available due to risk of __ __

Back 55

cardiac arrhythmias

Front 56

What is terfenadines carboxylic acid metabolite?

Back 56

fexofenadine

Front 57

fexofenadine accounts for the antihistaminic properties of terfenadine, which is very rapidly what? via what process?

Back 57

rapidly metabolized via CYP3A4-catalyzed oxidative processes.

Front 58

Cetirizine, the acid metabolite from oxidation of the primary ___ of the antihistamine ___

Back 58

alcohol of the antihistamine hydroxyzine,

Front 59

Cetirizine has what kind of duration of action and is highly selective for what receptors?

Back 59

It has a long duration of action and is highly selective for H1 receptors

Front 60

. No cardiotoxicity has been reported, but some drowsiness occurs (therefore it is categorized as both what?

Back 60

a first- and second-generation antihistamine

Front 61

What is the R-enantiomer of cetirizine

Back 61

levocetirizine

Front 62

Levocetirizine has higher affinity than its _-_____ for the ____ receptor (>30-fold) and is 20X more slowly ___ by the receptor

Back 62

S-enantiomer for the H1 receptor (>30-fold) and is 20X more slowly dissociated by the receptor

Front 63

What are the most familiar tricyclin antihistamines?

Back 63

loratadine(Claritin)and desloratadine(Clarinex)
azatadine

Front 64

Topical H1 Antihistamines

Topical application of H1 antihistamines to the eye is made to relieve

Back 64

to relieve itching, and eye effects

Front 65

Topical H1 Antihistamines

The density of mast cells in the ____is high, and the histamine concentrations in ____ ___ are significant in the ___allergic response.

Back 65

The density of mast cells in the conjunctiva is high, and the histamine concentrations in tear film are significant in the ocular allergic response.

Front 66

Topical H1 Antihistamines

From eye drops, only small amounts of the antihistamine (1–5%) penetrate the __

Back 66

cornea

Front 67

. From eye drops, only small amounts of the antihistamine (1–5%) penetrate the cornea. More of the compound is absorbed via the ___ and __ __ and still more ends up swallowed from the __ and the __ ___

Back 67

conjunctiva and nasal mucosa, and still more ends up swallowed from tearduct and nasal drainage

Front 68

Ketotifen is a topical antihistamine that has a puckered what? That gives what to the molecule?

Back 68

tricyclic ring system that gives the molecule chirality

Front 69

The____“chiral” forms of the drug are rapidly _____, however, and cannot be separated at ____ ____.

Back 69

The two “chiral” forms of the drug are rapidly intercoverting, however, and cannot be separated at room temperature.

Front 70

The H2 antihistamines are used in the treatment of what? What are they sold as?

Back 70

of duodenal ulcers, gastric ulcers, gastroesophageal reflux disease (GERD)

are sold OTC for acid indigestion

Front 71

Like H1 antihistamines, H2 antihistamines are inverse what? What do they block? They are what kind of molecule that closely resembles what?

Back 71

inverse agonists that block the basal level of activity at this receptor. They are partial agonist molecules very closely resembling histamine.

Front 72

What was one of the first H2 antihistamines

Back 72

Cimetidine

Front 73

Cimetidine was one of the first drugs, and has what kind of ring?

Back 73

imidazole ring like that of histamine.

Front 74

Cimetidine was one of the first drugs, and has an imidazole ring like that of histamine. The C-5 methyl group affords what?

Back 74

H2 selectivity; a four-atom side chain, which includes one sulfur atom (the sulfur atom increases potency compared to carbon and oxygen); and a terminal polar nonbasic unit, in this case an N-cyanoguanidine substituent.

Front 75

Guanidines substituted with electron-withdrawing groups have significantly decreased what compared to what? They are what at physiological pH?

Back 75

Guanidines substituted with electron-withdrawing groups have significantly decreased

Front 76

Antiulcer Agents – Proton Pump Inhibitors

The final step in acid secretion in parietal cells of the gastric mucosa is a process mediated by what?

Back 76

H+, K+-ATPase, the gastric proton pump.

Front 77

What are 2 Antiulcer Agents – Proton Pump Inhibitors?

Back 77

Omeprazole (Prilosec), lansoprazole (Prevacid

Front 78

Omeprazole (Prilosec), lansoprazole (Prevacid) and related analogues produce inhibition of what?

Back 78

stimulated gastric acid secretion irrespective of the receptor stimulation process

Front 79

Omeprazole (Prilosec), lansoprazole (Prevacid) and related analogues produce inhibition of stimulated gastric acid secretion irrespective of the receptor stimulation process. Nearly all the compounds are close structural relatives, being weakly what?

Back 79

basic 2-pyridyl-methylsulfinyl benzimidazoles.

Front 80

Antiulcer Agents – Proton Pump Inhibitors

Sulfoxides are generally represented with what structural formula?

Back 80

R-S(=O)-R', where R and R' are organic groups

Front 81

Antiulcer Agents – Proton Pump Inhibitors

Sulfoxides are generally represented with the structural formula R-S(=O)-R', where R and R' are organic groups. The bond between the sulfur and oxygen atoms differs from the ___ __ ___ between the ___ and ___ in ___

Back 81

conventional double bond between carbon and oxygen in, say, ketones.

Front 82

Antiulcer Agents – Proton Pump Inhibitors
T
he S-O bond has significant ____ character, with ___ charge centered on ___

Back 82

dipolar character, with negative charge centered on oxygen.

Front 83

A lone pair of electrons resides on the sulfur atom, giving it ___ geometry

Back 83

tetrahedral geometry

Front 84

When the two R groups are different, the sulfur is what? What is an example?

Back 84

is a chiral, for example, methylphenylsulfoxide.