Conjugates of catecholamines. 6. Synthesis and beta-adrenergic activity of N-(hydroxyalkyl)catecholamine derivatives.
A new series of catecholamines has been prepared in which the N-alkyl substituent of dl-epinephrine or dl-isoproterenol has been extended by a methylene chain terminated by a hydroxyl group or derived functionality (e.g., carbamate or ester). These functionalized catecholamines (congeners) and model compounds were prepared with the goal of eventual attachment to polymeric carrier molecules. The beta-adrenergic agonist activity of the derivatives was evaluated in vitro by measuring the intracellular accumulation of cyclic AMP in S49 mouse lymphoma cells and by the displacement of iodocyanopindolol (ICYP). A n-butylcarbamate derivative (compound 15) was the most active compound in this series with a potency 190 times greater than dl-isoproterenol in the S49 assay. The biological results indicate that minor modifications in structure in the N-alkyl substituent of the catecholamine can influence the pharmacologic activity.
Reitz
A B
AB
Avery
M A
MA
Rosenkranz
R P
RP
Verlander
M S
MS
Melmon
K L
KL
Hoffman
B B
BB
Akita
Y
Y
Castagnoli
N
N
Goodman
M
M
D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis*; D000818:Animals; D001667:Binding, Competitive; D002395:Catecholamines / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006900:Hydroxylation; D066298:In Vitro Techniques; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000494:pharmacology; D008223:Lymphoma / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D011433:Propranolol; D010869:Pindolol; D000242:Cyclic AMP; D007545:Isoproterenol