Structure-activity relationships of methoctramine-related polyamines as muscular nicotinic receptor noncompetitive antagonists. 3. Effect of inserting the tetraamine backbone into a macrocyclic structure.
The present article expands on the study of another aspect of structure-activity relationships of the polymethylene tetraamines, namely, the effect of inserting the tetraamine backbone into a macrocyclic structure. To this end, compounds 8-12 were designed by linking the two terminal nitrogen atoms of prototype methoctramine 2 to an aryl moiety. Alternatively, 2 was first modified to achieve compounds 6 and 7, which in turn were cyclized by linking the two terminal primary amine functions to a polyphenyl spacer, affording 13-20. All the compounds were tested on muscle-type nAChRs and most of them as well on AChE. Furthermore, selected compounds were tested also on peripheral M(2) and M(3) mAChRs. All these cyclic derivatives, like prototypes, were potent noncompetitive antagonists at both frog and Torpedo nAChRs, suggesting that polyamines do not need to be linear or in extended conformation to optimally interact with the nicotinic channel; rather, they may bind in a U-shaped conformation. Relative to muscarinic activity, macrocyclic compounds 10, 13, 14, and 20, in contrast with the profile displayed by 2, were almost devoid of affinity. It is derived that an aryl spacer is detrimental to the interaction of polyamines with mAChRs. Finally, all the diamine diamides investigated in this study were much less potent in inhibiting AChE activity than prototype 3, suggesting that a macrocyclic structure may not be suitable for AChE inhibition.
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Maria L
ML
Bolognesi
M Gabriele
MG
Bixel
Gabriella
G
Marucci
Manuela
M
Bartolini
Michael
M
Krauss
Piero
P
Angeli
Alessandra
A
Antonello
Michela
M
Rosini
Vincenzo
V
Tumiatti
Ferdinand
F
Hucho
Carlo
C
Melchiorre
D000110:Acetylcholinesterase / Q000737:chemistry; D000818:Animals; D016275:Atrial Function; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D003959:Diamines / Q000737:chemistry*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009132:Muscles / Q000378:metabolism*; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011898:Ranidae; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D017568:Rectus Abdominis / Q000187:drug effects / Q000502:physiology; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D003959:Diamines; D018733:Nicotinic Antagonists; D011073:Polyamines; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D000110:Acetylcholinesterase; C054938:methoctramine