Medchem Anithistamines EXAM I Flashcards
What are the important factors to design an Antihistamine agonist?
-identify the pharmacophore
-same size/shape
-maintain conformation
What are the important factors to design an Antihistamine antagonist?
-know the structure of the receptor
-same stereochemistry
-has to fit into the receptor
-doesn’t have to be structurally similar to endogenous ligand
What does the core structure (pharmacophore) of histamine look like?
-2 heteroatoms
-connected via 2 C atoms
->Antihistamine requires similar electron density to fit into the receptor
Why are 2nd Gen Antihistamines less sedative, and less toxic?
-more specific/efficient in blocking Histamine receptors
-more hydrophilic, less brain penetration
What does CYP metabolism have to do with less sedation in 2nd GEN Antihistamines?
-CYP metabolism only in 2ns GEN Antihistamines
-molecule is more water-soluble after CYP metabolism
-more hydrophilic drugs are less likely to cross the BBB
What other chemical properties make 2nd GEN drugs less drowsy?
-lower affinity to serotonin receptors (diphenhydramine 1st gen has a higher affinity to serotonin receptors (5-HT))
-higher affinity to efflux transporter in the brain (2nd gens are kicked out of the brain)
-amphoteric: ionizable at any physiological pH -> more ionic compounds are less likely to cross the BBB
Which antihistamine contains a piperazine ring?
-Cetirizine
-Levocetirizine (more active enantiomer - active metabolite)
-piperazine provides flexibility, making it fit better to the receptor
Which of the two is available in a larger dose?
Levocetirizine or Cetirizine
-Cetirizine (10 mg) - contains 50% inactive enantiomer
-it is cheaper to produce without separating both
Why does Loratidine not work effectively for some patients?
-Loratadine (Claritin) is activated by CYP3A4 and CYP2D6
-CYP2D6 is more involved in activation
-patients with certain CYP2D6 alleles will experience less or no function of the drug
(some of the alleles also impact opioid metabolism)
Why does Fluoxetine (antidepressant) cause drowsiness?
-lipophilic - it crosses the BBB
-similarites to Histamines (Antihistamines)
-they bind to Histamine (H3) receptors in the brain to some extent -> causing drowsiness
Which drug improves conditions in the nasal cavities and targets adrenergic receptors?
-Adrenergic agonists -> Decongestants
-target Alpha receptors
-Vasoconstriction -> to decrease swelling in the nose
To which group of molecules do decongestants belong?
-Catecholamines
-like Epinephrine, Norepinephrine, Dopamine
What are the characteristics of a catecholamine?
-Catecholring with 2 hydroxyl groups (binding to Asp on target)
-Ethylamine: alpha and beta carbon and Amine group (binding to Serine on the target)
SAR of Adrenergic Agonists
What makes Catecholamine specifically bind to alpha or beta receptors?
alpha:
-small functional group on R1 and R2 (H, CH3)
-3-OH on R3
beta:
-large functional group on R1 and R2 (t-butyl, large c-chains)
-4-OH on R3
-3,4 Hydroxyl on R3 promote alpha and beta selectivity
Where are the chiral centers located?
alpha and beta carbons
-at the alpha carbon: anything else than a H will create a chiral center
