SAR final

Question 1

As R1 increases what happens to physiological activity?

Answer 1

As R1 increases in size alpha activity decreases and Beta activity increases

Question 2

SAR for TCAs

1. Amine substitution
2. _ carbons between tricyclic ring and amine
3. _____ on tricyclic ring increses affinity for?

Answer 2

• Tertiary
  
  • S reuptake > NE reuptake
  • More orthostatic hypotension than secondary
  • Generally more anticholinergic SEs
• Secondary
  
  • NE reuptake > S
  • less sedation compared to tertiaty
• 3 carbons between tricyclic ring system and amine
• Halogen on tricyclic system increases affinity for 5-HT transporter

Question 3

SAR of stimulants S configuration=?

R=?

What other things

Answer 3

• S= Stimulant
• R= Hallucinogen
• Adding methyl group increases potency
• 2>1>>>3

Question 4

Cannabinoid SAR

Metabolism?

Answer 4

• Adding 11- OH group increases potency
• Moving 9-10 dbl bond to 9-8 increases potency
• Replace penyl with a 1,1 dimethylheptyl increases potency
• Major metabolite Allylic hydroxylation at 11 group
• Omega minus one
• Conjugation at phenol

Question 5

SAR of indolealkylamines and related agents

Answer 5

Need alpha carbon substitution to block MAO metabolism or di substitution on the Nitrogen

Question 6

SAR for amphetamine like stimulants and DOM-like action of phenylisopropylamines

Answer 6

Ketone increases potency for both.

Question 7

Opioid peptide SAR

Answer 7

• All endogenous opiod peptides have Leu or Met enkephalin as their first five AAs
• Tyrosine at the first position is essential for activity
• After the phenolic group and amine in tyrosine, the next essential feature is the phenyl group of Phe4.
• Enkephalins like have different conformations
• Replacement of L-amino acids with D-amino acids can make peptides resistant to peptidases
• Converting terminal carboxy group into alcohol or amide protects peptide from carboxy peptidases prolonged action
• Introduction of unnatural amino acids or bulky groups to enkephalins affects conformation
• Restriction of conformational mobility has led to receptor selective peptides

Question 8

Classical morphine SAR

What is absolutely essential for maximal activity?

Answer 8

OH at the 3 position

Question 9

SAR of Thiazide Diuretics?

Answer 9

• C7-position: Sulfonamide group is required for activity
• C6-position (R1): Electron-withdrawing group (e.g. Cl, CF3 etc) required for activity
• 3–4-position: Saturation of the double bond results in more potent (~ 10-fold) analogs
• C3-position (R2): Lipophilic group improves diuretic potency
• 2-position (R3): N-alkyl substitution increases the duration of diuretic action

Question 10

SAR of ACE Is

Answer 10

• The N-ring carboxylic acid is essential (mimics the C-terminal carboxylate of ACE substrates)
• Large hydrophobic functionalities in the N-ring increases potency
• Zn-ion binding groups (sulfhydryl, carboxylate, phosphinic acid etc) required for potency
• ‘X’ is usually methyl (mimics the side-chain of alanine), the exception being Lisinopril
• For optimum activity, stereochemistry should be consistent with natural L-amino acid

Question 11

Pka SAR of Histamine

Answer 11