Further investigation on methoctramine-related tetraamines: effects of terminal N-substitution and of chain length separating the four nitrogens on M2 muscarinic receptor blocking activity.
A series of tetraamines related to methoctramine (1) was synthesized and evaluated for its blocking activity on M2 and M3 muscarinic receptors of guinea pig left atria and ileum, respectively. Thus, tetraamines 2-7 were synthesized to evaluate the effect on affinity of replacing the 2-methoxybenzyl moiety of methoctramine by a phenethyl-type substituent. Furthermore, tetraamines 8 and 9 were investigated to analyze the effect on affinity of the chain length separating the inner nitrogens and the inner from outer nitrogens while keeping the total distance between the two outer nitrogens equal to that of methoctramine. It turned out that all the tetraamines investigated, although showing a significant affinity, were less active than methoctramine at M2 muscarinic receptors. The underlying drug-receptor interaction mechanisms are discussed.
Minarini
A
A
Dipartimento di Scienze Farmaceutiche, Università di Bologna, Italy.
Budriesi
R
R
Chiarini
A
A
Melchiorre
C
C
Tumiatti
V
V
D000818:Animals; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003959:Diamines / Q000494:pharmacology*; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018727:Muscarinic Antagonists; D009130:Muscle, Smooth / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared
D003959:Diamines; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D002217:Carbachol; C054938:methoctramine