Exam 4 - Lecture 41, Medical Chemistry of Adrenergic Agonists

about 95% uptake by uptake mechanism about 5% if metabolized by COMT + Diffusion

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

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

CH3 = a2>a1 CH2CH3 = B > a 1R, 2S = direct acting (a2>a1) 1R, 2R = indirectly acting

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

1R,2S = direct acting, also indirect acting so its mixed 1R, 2R = indirect acting 1S,2R = indirect acting

protonated at physiological pH Vasoconstrictors or vasopressors N is part of ring

adding another N, so have 1 N in ring, and 1 in linked between

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

pro drug, more lipophilic and then chopped to make colterol has longer duration of action, 8 hr

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

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