Conjugates of catecholamines. 5. Synthesis and beta-adrenergic activity of N-(aminoalkyl)norepinephrine derivatives.
A novel series of N-aminoalkyl congeners and model derivatives of norepinephrine has been synthesized. Compounds that were structurally related to epinephrine were prepared from fully protected intermediates. Alternatively, isoproterenol-related compounds were synthesized via reductive amination of preformed methyl ketone derivatives with norepinephrine. The beta-adrenergic activities of these new compounds were assessed through measurement of intracellular cyclic AMP accumulation in S49 mouse lymphoma cells and displacement of iodocyanopindolol (ICYP) from membrane preparations. Congeners that contained an underivatized primary amine function exhibited virtually no activity in these assays. However, when this amine function was acylated (e.g., to an amide, carbamate, urea, sulfonamide, etc.), the products exhibited generally increased beta-adrenergic activity, which was, however, strongly dependent on the nature of the acylating group and also the length of the spacer. In particular, a benzyl carbamate derivative containing a branched, seven-carbon spacer group was 40 times more potent than isoproterenol in the in vitro S49 assay.
Reitz
A B
AB
Sonveaux
E
E
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; D000242:Cyclic AMP / Q000378:metabolism; D066298:In Vitro Techniques; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000494:pharmacology; D008223:Lymphoma / Q000378:metabolism; D051379:Mice; D009638:Norepinephrine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; 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; D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D011433:Propranolol; D010869:Pindolol; D000242:Cyclic AMP; D007545:Isoproterenol; D009638:Norepinephrine