Exam 4 - Lecture 41, Medical Chemistry of Adrenergic Agonists Flashcards
NE reuptake
about 95% uptake by uptake mechanism
about 5% if metabolized by COMT + Diffusion
Effector interaction, NE with receptor
positively charged amine function - ionic or salt bridge bond with Asp113 in TMD3
Catechol hydroxyls - H bond with ser204 and ser207 of TMD5
Catechol ring - interacts with phenylalanine residues of TMD6
Substitution on amino nitrogen (variation of R1)
Increasing methyl groups gives B selectivity over A
Bigger R1 brings back a affinity, without intrinsic activity (a/b antagonist)
NE - 0 CH3
Epinephrine - 1 CH3
Isoproterenol - 2 CH3
Colterol - 3 CH3
Substitution of a to the basic nitrogen (variation of R2)
CH3 = a2>a1 CH2CH3 = B > a
1R, 2S = direct acting (a2>a1)
1R, 2R = indirectly acting
Substitution on aromatic ring (variation of R3)
if only 3’-OH is present than compound has reduced a activity and almost no b activity…leading to a-selective agonist
moving 4 to 5, make more B2>B1
Extending 3 by 1 C = B2>B1
Stereochemistry C-1 and C-2 Ephedrine
1R,2S = direct acting, also indirect acting so its mixed
1R, 2R = indirect acting
1S,2R = indirect acting
2-Arylimidazolines
protonated at physiological pH
Vasoconstrictors or vasopressors
N is part of ring
2-Aminoimidazolines
adding another N, so have 1 N in ring, and 1 in linked between
Clonidine confirmation
off planar confirmation is important for way it its in receptor
substituting Cl with CH3, will make it have shorter duration of action/less stable
Bitolterol
pro drug, more lipophilic and then chopped to make colterol
has longer duration of action, 8 hr
Salmeterol
After anchoring, remains part of molecule can pivot on and off the normal b2 binding sites of Asp 113 (TMD3) and Ser 204/207 of TMD5
12 hr duration vs 4 hrs of Albuterol
Dobutamine
S isomer exhibits B1 agonist activity and also powerful a1 agonist and vasopressor
R is a1 antagonist
So give as racemate so the a effects cancel and leaves B effects
